Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mutations in key driver genes of pancreatic cancer: molecularly targeted therapies and other clinical implications

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a minimal difference between its incidence rate and mortality rate. Advances in oncology over the past several decades have dramatically improved the overall survival of patients with multiple cancers due to the implementation of new techniques in early diagnosis, therapeutic drugs, and personalized therapy. However, pancreatic cancers remain recalcitrant, with a 5-year relative survival rate of <9%. The lack of measures for early diagnosis, strong resistance to chemotherapy, ineffective adjuvant chemotherapy and the unavailability of molecularly targeted therapy are responsible for the high mortality rate of this notorious disease. Genetically, PDAC progresses as a complex result of the activation of oncogenes and inactivation of tumor suppressors. Although next-generation sequencing has identified numerous new genetic alterations, their clinical implications remain unknown. Classically, oncogenic mutations in genes such as KRAS and loss-of-function mutations in tumor suppressors, such as TP53, CDNK2A, DPC4/SMAD4, and BRCA2, are frequently observed in PDAC. Currently, research on these key driver genes is still the main focus. Therefore, studies assessing the functions of these genes and their potential clinical implications are of paramount importance. In this review, we summarize the biological function of key driver genes and pharmaceutical targets in PDAC. In addition, we conclude the results of molecularly targeted therapies in clinical trials and discuss how to utilize these genetic alterations in further clinical practice.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Mutation profile of pancreatic cancer in the TCGA dataset.
Fig. 2: Classical progression model of pancreatic cancer.
Fig. 3: Pathways of key driver genes and therapeutic targets in pancreatic cancer.
Fig. 4: DNA damage repair pathway and the mechanism of PARP inhibitors.

References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–21.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Neoptolemos JP, Kleeff J, Michl P, Costello E, Greenhalf W, Palmer DH. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol. 2018;15:333–48.

    PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Maisonneuve P. Epidemiology and burden of pancreatic cancer. Presse Med. 2019;48:e113–e23.

    PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Rawla P, Sunkara T, Gaduputi V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J Oncol. 2019;10:10–27.

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.

    Article  CAS  Google Scholar 

  8. 8.

    Maitra A, Fukushima N, Takaori K, Hruban RH. Precursors to invasive pancreatic cancer. Adv Anat Pathol. 2005;12:81–91.

    PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47–52.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495–501.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491:399–405.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Maitra A, Hruban RH. Pancreatic cancer. Annu Rev Pathol. 2008;3:157–88.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Makohon-Moore A, Iacobuzio-Donahue CA. Pancreatic cancer biology and genetics from an evolutionary perspective. Nat Rev Cancer. 2016;16:553–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res. 2000;6:2969–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988;53:549–54.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014;371:2140–1.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  18. 18.

    Haigis KM. KRAS alleles: the devil is in the detail. Trends Cancer. 2017;3:686–97.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    di Magliano MP, Logsdon CD. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology. 2013;144:1220–9.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    Buscail L, Bournet B, Cordelier P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2020;17:153–68.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Zeitouni D, Pylayeva-Gupta Y, Der CJ, Bryant KL. KRAS mutant pancreatic cancer: no lone path to an effective treatment. Cancers (Basel). 2016;8:45.

    Article  CAS  Google Scholar 

  22. 22.

    Collins MA, Bednar F, Zhang Y, Brisset JC, Galban S, Galban CJ, et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest. 2012;122:639–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Omori Y, Ono Y, Tanino M, Karasaki H, Yamaguchi H, Furukawa T, et al. Pathways of progression from intraductal papillary mucinous neoplasm to pancreatic ductal adenocarcinoma based on molecular features. Gastroenterology. 2019;156:647–61 e2.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Tape CJ, Ling S, Dimitriadi M, McMahon KM, Worboys JD, Leong HS, et al. Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell. 2016;165:1818.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 2012;149:656–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Liang C, Qin Y, Zhang B, Ji S, Shi S, Xu W, et al. Metabolic plasticity in heterogeneous pancreatic ductal adenocarcinoma. Biochim Biophys Acta. 2016;1866:177–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013;496:101–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, Hackett S, et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature. 2013;497:633–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003;4:437–50.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Collins MA, Brisset JC, Zhang Y, Bednar F, Pierre J, Heist KA, et al. Metastatic pancreatic cancer is dependent on oncogenic Kras in mice. PLoS One. 2012;7:e49707.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378:607–20.

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Mann KM, Ying H, Juan J, Jenkins NA, Copeland NG. KRAS-related proteins in pancreatic cancer. Pharmacol Ther. 2016;168:29–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Ji S, Qin Y, Shi S, Liu X, Hu H, Zhou H, et al. ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer. Cell Res. 2015;25:561–73.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Ji SR, Qin Y, Liang C, Huang R, Shi S, Liu J, et al. FBW7 (F-box andWDRepeat Domain-Containing 7) negatively regulates glucose metabolism by targeting the c-Myc/TXNIP (thioredoxin-binding protein) axis in pancreatic cancer. Clin Cancer Res. 2016;22:3950–60.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Liang C, Qin Y, Zhang B, Ji S, Shi S, Xu W, et al. Oncogenic KRAS targets MUC16/CA125 in pancreatic ductal adenocarcinoma. Mol Cancer Res. 2017;15:201–12.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Zhang L, Sanagapalli S, Stoita A. Challenges in diagnosis of pancreatic cancer. World J Gastroenterol. 2018;24:2047–60.

    PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Wilentz RE, Chung CH, Sturm PD, Musler A, Sohn TA, Offerhaus GJ, et al. K-ras mutations in the duodenal fluid of patients with pancreatic carcinoma. Cancer-Am Cancer Soc. 1998;82:96–103.

    CAS  Google Scholar 

  38. 38.

    Lisotti A, Frazzoni L, Fuccio L, Serrani M, Cominardi A, Bazzoli F, et al. Repeat EUS-FNA of pancreatic masses after nondiagnostic or inconclusive results: systematic review and meta-analysis. Gastrointest Endosc. 2020;91:1234–41.e4.

    PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Bournet B, Buscail C, Muscari F, Cordelier P, Buscail L. Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities. Eur J Cancer. 2016;54:75–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Khalid A, Dewitt J, Ohori NP, Chen JH, Fasanella KE, Sanders M, et al. EUS-FNA mutational analysis in differentiating autoimmune pancreatitis and pancreatic cancer. Pancreatology. 2011;11:482–6.

    PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Cohen JD, Javed AA, Thoburn C, Wong F, Tie J, Gibbs P, et al. Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers. Proc Natl Acad Sci USA. 2017;114:10202–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Bernard V, Kim DU, San Lucas FA, Castillo J, Allenson K, Mulu FC, et al. Circulating nucleic acids are associated with outcomes of patients with pancreatic cancer. Gastroenterology. 2019;156:108–18 e4.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Watanabe F, Suzuki K, Tamaki S, Abe I, Endo Y, Takayama Y, et al. Longitudinal monitoring of KRAS-mutated circulating tumor DNA enables the prediction of prognosis and therapeutic responses in patients with pancreatic cancer. PLoS One. 2019;14:e0227366.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Perets R, Greenberg O, Shentzer T, Semenisty V, Epelbaum R, Bick T, et al. Mutant KRAS circulating tumor DNA is an accurate tool for pancreatic cancer monitoring. Oncologist. 2018;23:566–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Allenson K, Castillo J, San Lucas FA, Scelo G, Kim DU, Bernard V, et al. High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients. Ann Oncol. 2017;28:741–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Yang S, Che SP, Kurywchak P, Tavormina JL, Gansmo LB, Correa de Sampaio P, et al. Detection of mutant KRAS and TP53 DNA in circulating exosomes from healthy individuals and patients with pancreatic cancer. Cancer Biol Ther. 2017;18:158–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Fiala C, Diamandis EP. Utility of circulating tumor DNA in cancer diagnostics with emphasis on early detection. BMC Med. 2018;16:166.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Stephen AG, Esposito D, Bagni RK, McCormick F. Dragging ras back in the ring. Cancer Cell. 2014;25:272–81.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  49. 49.

    Winter JJ, Anderson M, Blades K, Brassington C, Breeze AL, Chresta C, et al. Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation. J Med Chem. 2015;58:2265–74.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Maurer T, Garrenton LS, Oh A, Pitts K, Anderson DJ, Skelton NJ, et al. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc Natl Acad Sci USA. 2012;109:5299–304.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Lu S, Jang H, Zhang J, Nussinov R. Inhibitors of Ras-SOS interactions. ChemMedChem 2016;11:814–21.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Holderfield M. Efforts to develop KRAS inhibitors. Cold Spring Harb Perspect Med. 2018;8:a031864.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. 53.

    Van Cutsem E, van de Velde H, Karasek P, Oettle H, Vervenne WL, Szawlowski A, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol. 2004;22:1430–8.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  54. 54.

    Cox AD, Der CJ, Philips MR. Targeting RAS membrane association: back to the future for anti-RAS drug discovery? Clin Cancer Res. 2015;21:1819–27.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Gong J, Mita MM. Activated ras signaling pathways and reovirus oncolysis: an update on the mechanism of preferential reovirus replication in cancer cells. Front Oncol. 2014;4:167.

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Noonan AM, Farren MR, Geyer SM, Huang Y, Tahiri S, Ahn D, et al. Randomized phase 2 trial of the oncolytic virus pelareorep (Reolysin) in upfront treatment of metastatic pancreatic adenocarcinoma. Mol Ther. 2016;24:1150–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Zorde Khvalevsky E, Gabai R, Rachmut IH, Horwitz E, Brunschwig Z, Orbach A, et al. Mutant KRAS is a druggable target for pancreatic cancer. Proc Natl Acad Sci USA. 2013;110:20723–8.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  58. 58.

    Strand MS, Krasnick BA, Pan H, Zhang X, Bi Y, Brooks C, et al. Precision delivery of RAS-inhibiting siRNA to KRAS driven cancer via peptide-based nanoparticles. Oncotarget. 2019;10:4761–75.

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Shin SH, Kim SC, Hong SM, Kim YH, Song KB, Park KM, et al. Genetic alterations of K-ras, p53, c-erbB-2, and DPC4 in pancreatic ductal adenocarcinoma and their correlation with patient survival. Pancreas. 2013;42:216–22.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Sinn BV, Striefler JK, Rudl MA, Lehmann A, Bahra M, Denkert C, et al. KRAS mutations in codon 12 or 13 are associated with worse prognosis in pancreatic ductal adenocarcinoma. Pancreas. 2014;43:578–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Ogura T, Yamao K, Hara K, Mizuno N, Hijioka S, Imaoka H, et al. Prognostic value of K-ras mutation status and subtypes in endoscopic ultrasound-guided fine-needle aspiration specimens from patients with unresectable pancreatic cancer. J Gastroenterol. 2013;48:640–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. 62.

    Heinemann V, Vehling-Kaiser U, Waldschmidt D, Kettner E, Marten A, Winkelmann C, et al. Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’ (AIO-PK0104). Gut. 2013;62:751–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63.

    Schultheis B, Reuter D, Ebert MP, Siveke J, Kerkhoff A, Berdel WE, et al. Gemcitabine combined with the monoclonal antibody nimotuzumab is an active first-line regimen in KRAS wildtype patients with locally advanced or metastatic pancreatic cancer: a multicenter, randomized phase IIb study. Ann Oncol. 2017;28:2429–35.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    Lee JW, Lee JH, Shim BY, Kim SH, Chung MJ, Kye BH, et al. KRAS mutation status is not a predictor for tumor response and survival in rectal cancer patients who received preoperative radiotherapy with 5-fluoropyrimidine followed by curative surgery. Med (Baltim). 2015;94:e1284.

    CAS  Article  Google Scholar 

  65. 65.

    Kim ST, Lim DH, Jang KT, Lim T, Lee J, Choi YL, et al. Impact of KRAS mutations on clinical outcomes in pancreatic cancer patients treated with first-line gemcitabine-based chemotherapy. Mol Cancer Ther. 2011;10:1993–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Propper D, Davidenko I, Bridgewater J, Kupcinskas L, Fittipaldo A, Hillenbach C, et al. Phase II, randomized, biomarker identification trial (MARK) for erlotinib in patients with advanced pancreatic carcinoma. Ann Oncol. 2014;25:1384–90.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    Kong Y, Sharma RB, Nwosu BU, Alonso LC. Islet biology, the CDKN2A/B locus and type 2 diabetes risk. Diabetologia. 2016;59:1579–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell. 2006;127:265–75.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature. 2006;443:453–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. 70.

    Taneera J, Fadista J, Ahlqvist E, Zhang M, Wierup N, Renstrom E, et al. Expression profiling of cell cycle genes in human pancreatic islets with and without type 2 diabetes. Mol Cell Endocrinol. 2013;375:35–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  71. 71.

    Molofsky AV, Slutsky SG, Joseph NM, He S, Pardal R, Krishnamurthy J, et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature. 2006;443:448–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, et al. Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004;114:1299–307.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Ozenne P, Eymin B, Brambilla E, Gazzeri S. The ARF tumor suppressor: structure, functions and status in cancer. Int J Cancer. 2010;127:2239–47.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Bardeesy N, Aguirre AJ, Chu GC, Cheng KH, Lopez LV, Hezel AF, et al. Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci USA. 2006;103:5947–52.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Ghiorzo P, Pastorino L, Bonelli L, Cusano R, Nicora A, Zupo S, et al. INK4/ARF germline alterations in pancreatic cancer patients. Ann Oncol. 2004;15:70–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. 76.

    Romagosa C, Simonetti S, Lopez-Vicente L, Mazo A, Lleonart ME, Castellvi J, et al. p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene. 2011;30:2087–97.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  77. 77.

    Singh SK, Ellenrieder V. Senescence in pancreatic carcinogenesis: from signalling to chromatin remodelling and epigenetics. Gut. 2013;62:1364–72.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Fukushima N, Sato N, Ueki T, Rosty C, Walter KM, Wilentz RE, et al. Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. Am J Pathol. 2002;160:1573–81.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Azzopardi S, Pang S, Klimstra DS, Du YN. p53 and p16(Ink4a)/p19(Arf) loss promotes different pancreatic tumor types from PyMT-expressing progenitor cells. Neoplasia. 2016;18:610–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet. 1994;8:27–32.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  81. 81.

    House MG, Herman JG, Guo MZ, Hooker CM, Schulick RD, Lillemoe KD, et al. Aberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms. Ann Surg. 2003;238:423–31. discussion 31-2

    PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Chen J, Li D, Killary AM, Sen S, Amos CI, Evans DB, et al. Polymorphisms of p16, p27, p73, and MDM2 modulate response and survival of pancreatic cancer patients treated with preoperative chemoradiation. Ann Surg Oncol. 2009;16:431–9.

    PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    Luo Y, Tian L, Feng Y, Yi M, Chen X, Huang Q. The predictive role of p16 deletion, p53 deletion, and polysomy 9 and 17 in pancreatic ductal adenocarcinoma. Pathol Oncol Res. 2013;19:35–40.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  84. 84.

    Oshima M, Okano K, Muraki S, Haba R, Maeba T, Suzuki Y, et al. Immunohistochemically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer. Ann Surg. 2013;258:336–46.

    PubMed  Article  PubMed Central  Google Scholar 

  85. 85.

    Beaver JA, Amiri-Kordestani L, Charlab R, Chen W, Palmby T, Tilley A, et al. FDA approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2015;21:4760–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 86.

    Chou A, Froio D, Nagrial AM, Parkin A, Murphy KJ, Chin VT, et al. Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. Gut. 2018;67:2142–55.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    Junttila MR, Evan GI. p53-a Jack of all trades but master of none. Nat Rev Cancer. 2009;9:821–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    Kastenhuber ER, Lowe SW. Putting p53 in Context. Cell. 2017;170:1062–78.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Menendez D, Inga A, Resnick MA. The expanding universe of p53 targets. Nat Rev Cancer. 2009;9:724–37.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2:a001008.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. 91.

    Mantovani F, Collavin L, Del, Sal G. Mutant p53 as a guardian of the cancer cell. Cell Death Differ. 2019;26:199–212.

    PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

    Zhang C, Liu J, Liang Y, Wu R, Zhao Y, Hong X, et al. Tumour-associated mutant p53 drives the Warburg effect. Nat Commun. 2013;4:2935.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  93. 93.

    Baumgart M, Werther M, Bockholt A, Scheurer M, Ruschoff J, Dietmaier W, et al. Genomic instability at both the base pair level and the chromosomal level is detectable in earliest PanIN lesions in tissues of chronic pancreatitis. Pancreas. 2010;39:1093–103.

    PubMed  Article  PubMed Central  Google Scholar 

  94. 94.

    Morton JP, Timpson P, Karim SA, Ridgway RA, Athineos D, Doyle B, et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc Natl Acad Sci USA. 2010;107:246–51.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. 95.

    Lillemoe KD, Hwang, Thompson JC, Townsend CM, Vickers SM, Beauchamp RD, et al. Gene therapy for primary and metastatic pancreatic cancer with intraperitoneal retroviral vector bearing the wild-type p53 gene - Discussion. Surgery. 1998;124:150–1.

    Article  Google Scholar 

  96. 96.

    Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005;7:469–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  97. 97.

    Smith RA, Tang J, Tudur-Smith C, Neoptolemos JP, Ghaneh P. Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer. Br J Cancer. 2011;104:1440–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Vitellius C, Eymerit-Morin C, Luet D, Fizanne L, Foubert F, Bertrais S, et al. Relationship between the expression of O(6)-methylguanine-DNA methyltransferase (MGMT) and p53, and the clinical response in metastatic pancreatic adenocarcinoma treated with FOLFIRINOX. Clin Drug Investig. 2017;37:669–77.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  99. 99.

    Striefler JK, Sinn M, Pelzer U, Juhling A, Wislocka L, Bahra M, et al. P53 overexpression and Ki67-index are associated with outcome in ductal pancreatic adenocarcinoma with adjuvant gemcitabine treatment. Pathol Res Pr. 2016;212:726–34.

    CAS  Article  Google Scholar 

  100. 100.

    Galmarini CM, Clarke ML, Falette N, Puisieux A, Mackey JR, Dumontet C. Expression of a non-functional p53 affects the sensitivity of cancer cells to gemcitabine. Int J Cancer. 2002;97:439–45.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  101. 101.

    Xu J, Wang J, Hu Y, Qian J, Xu B, Chen H, et al. Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity. Cell Death Dis. 2014;5:e1108.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Parrales A, Iwakuma T. Targeting oncogenic mutant p53 for cancer therapy. Front Oncol. 2015;5:288.

    PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Lambert JM, Gorzov P, Veprintsev DB, Soderqvist M, Segerback D, Bergman J, et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell. 2009;15:376–88.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  104. 104.

    Izetti P, Hautefeuille A, Abujamra AL, de Farias CB, Giacomazzi J, Alemar B, et al. PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines. Invest New Drugs. 2014;32:783–94.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. 105.

    Li D, Marchenko ND, Moll UM. SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis. Cell Death Differ. 2011;18:1904–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Moser C, Lang SA, Hackl C, Wagner C, Scheiffert E, Schlitt HJ, et al. Targeting HSP90 by the novel inhibitor NVP-AUY922 reduces growth and angiogenesis of pancreatic cancer. Anticancer Res. 2012;32:2551–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Nagaraju GP, Mezina A, Shaib WL, Landry J, El-Rayes BF. Targeting the Janus-activated kinase-2-STAT3 signalling pathway in pancreatic cancer using the HSP90 inhibitor ganetespib. Eur J Cancer. 2016;52:109–19.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. 108.

    Renouf DJ, Hedley D, Krzyzanowska MK, Schmuck M, Wang L, Moore MJ. A phase II study of the HSP90 inhibitor AUY922 in chemotherapy refractory advanced pancreatic cancer. Cancer Chemother Pharmacol. 2016;78:541–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. 109.

    Xu J, Singh A, Amiji MM. Redox-responsive targeted gelatin nanoparticles for delivery of combination wt-p53 expressing plasmid DNA and gemcitabine in the treatment of pancreatic cancer. BMC Cancer. 2014;14:75.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. 110.

    Chung V, Kos FJ, Hardwick N, Yuan Y, Chao J, Li D, et al. Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers. Clin Transl Oncol. 2019;21:363–72.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    Wang Y, Li J, Booher RN, Kraker A, Lawrence T, Leopold WR, et al. Radiosensitization of p53 mutant cells by PD0166285, a novel G2 checkpoint abrogator. Cancer Res. 2001;61:8211–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Cuneo KC, Morgan MA, Sahai V, Schipper MJ, Parsels LA, Parsels JD, et al. Dose escalation trial of the Wee1 inhibitor adavosertib (AZD1775) in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer. J Clin Oncol. 2019;37:2643–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, et al. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA. 2016;315:1844–53.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. 114.

    Mantovani F, Walerych D, Sal GD. Targeting mutant p53 in cancer: a long road to precision therapy. FEBS J. 2017;284:837–50.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  115. 115.

    McCarthy AJ, Chetty R. Smad4/DPC4. J Clin Pathol. 2018;71:661–4.

    PubMed  Article  PubMed Central  Google Scholar 

  116. 116.

    Wrana JL. The secret life of Smad4. Cell. 2009;136:13–4.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  117. 117.

    Dupont S, Zacchigna L, Cordenonsi M, Soligo S, Adorno M, Rugge M, et al. Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase. Cell. 2005;121:87–99.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  118. 118.

    Dupont S, Mamidi A, Cordenonsi M, Montagner M, Zacchigna L, Adorno M, et al. FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination. Cell. 2009;136:123–35.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 119.

    Zhao M, Mishra L, Deng CX. The role of TGF-beta/SMAD4 signaling in cancer. Int J Biol Sci. 2018;14:111–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Grau AM, Zhang L, Wang W, Ruan S, Evans DB, Abbruzzese JL, et al. Induction of p21waf1 expression and growth inhibition by transforming growth factor beta involve the tumor suppressor gene DPC4 in human pancreatic adenocarcinoma cells. Cancer Res. 1997;57:3929–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Heldin CH, Vanlandewijck M, Moustakas A. Regulation of EMT by TGFbeta in cancer. FEBS Lett. 2012;586:1959–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  122. 122.

    Furukawa T, Sunamura M, Horii A. Molecular mechanisms of pancreatic carcinogenesis. Cancer Sci. 2006;97:1–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  123. 123.

    Wilentz RE, Su GH, Dai JL, Sparks AB, Argani P, Sohn TA, et al. Immunohistochemical labeling for dpc4 mirrors genetic status in pancreatic adenocarcinomas: a new marker of DPC4 inactivation. Am J Pathol. 2000;156:37–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, et al. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 2000;60:2002–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J, Olson P, et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 2006;20:3130–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Whittle MC, Izeradjene K, Rani PG, Feng L, Carlson MA, DelGiorno KE, et al. RUNX3 controls a metastatic switch in pancreatic ductal adenocarcinoma. Cell. 2015;161:1345–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    Liang C, Shi S, Qin Y, Meng Q, Hua J, Hu Q, et al. Localisation of PGK1 determines metabolic phenotype to balance metastasis and proliferation in patients with SMAD4-negative pancreatic cancer. Gut. 2020;69:888–900.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  128. 128.

    Liang C, Xu J, Meng Q, Zhang B, Liu J, Hua J, et al. TGFB1-induced autophagy affects the pattern of pancreatic cancer progression in distinct ways depending on SMAD4 status. Autophagy. 2020;16:486–500.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  129. 129.

    David CJ, Huang YH, Chen M, Su J, Zou Y, Bardeesy N, et al. TGF-beta tumor suppression through a lethal EMT. Cell. 2016;164:1015–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527:525–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Wang F, Xia X, Yang C, Shen J, Mai J, Kim HC, et al. SMAD4 gene mutation renders pancreatic cancer resistance to radiotherapy through promotion of autophagy. Clin Cancer Res. 2018;24:3176–85.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Biankin AV, Morey AL, Lee CS, Kench JG, Biankin SA, Hook HC, et al. DPC4/Smad4 expression and outcome in pancreatic ductal adenocarcinoma. J Clin Oncol. 2002;20:4531–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  133. 133.

    Blackford A, Serrano OK, Wolfgang CL, Parmigiani G, Jones S, Zhang X, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009;15:4674–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Singh P, Srinivasan R, Wig JD. SMAD4 genetic alterations predict a worse prognosis in patients with pancreatic ductal adenocarcinoma. Pancreas. 2012;41:541–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  135. 135.

    Bachet JB, Marechal R, Demetter P, Bonnetain F, Couvelard A, Svrcek M, et al. Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma. Ann Oncol. 2012;23:2327–35.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  136. 136.

    Iacobuzio-Donahue CA, Fu B, Yachida S, Luo M, Abe H, Henderson CM, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27:1806–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Crane CH, Varadhachary GR, Yordy JS, Staerkel GA, Javle MM, Safran H, et al. Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression. J Clin Oncol. 2011;29:3037–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Winter JM, Tang LH, Klimstra DS, Liu W, Linkov I, Brennan MF, et al. Failure patterns in resected pancreas adenocarcinoma: lack of predicted benefit to SMAD4 expression. Ann Surg. 2013;258:331–5.

    PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Wang H, Stephens B, Von Hoff DD, Han H. Identification and characterization of a novel anticancer agent with selectivity against deleted in pancreatic cancer locus 4 (DPC4)-deficient pancreatic and colon cancer cells. Pancreas. 2009;38:551–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  140. 140.

    Wang H, Han H, Von, Hoff DD. Identification of an agent selectively targeting DPC4 (deleted in pancreatic cancer locus 4)-deficient pancreatic cancer cells. Cancer Res. 2006;66:9722–30.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  141. 141.

    Hong E, Park S, Ooshima A, Hong CP, Park J, Heo JS, et al. Inhibition of TGF-beta signalling in combination with nal-IRI plus 5-Fluorouracil/Leucovorin suppresses invasion and prolongs survival in pancreatic tumour mouse models. Sci Rep. 2020;10:2935.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Dey P, Baddour J, Muller F, Wu CC, Wang H, Liao WT, et al. Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer. Nature. 2017;542:119–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. 143.

    Holter S, Borgida A, Dodd A, Grant R, Semotiuk K, Hedley D, et al. Germline BRCA mutations in a large clinic-based cohort of patients with pancreatic adenocarcinoma. J Clin Oncol. 2015;33:3124–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  144. 144.

    Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T, Hall MJ, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381:317–27.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108:171–82.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  146. 146.

    D’Andrea AD. Susceptibility pathways in Fanconi’s anemia and breast cancer. N Engl J Med. 2010;362:1909–19.

    PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    Kowalewski A, Szylberg L, Saganek M, Napiontek W, Antosik P, Grzanka D. Emerging strategies in BRCA-positive pancreatic cancer. J Cancer Res Clin Oncol. 2018;144:1503–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Golan T, Kanji ZS, Epelbaum R, Devaud N, Dagan E, Holter S, et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer. 2014;111:1132–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. 149.

    Palacio S, McMurry HS, Ali R, Donenberg T, Silva-Smith R, Wideroff G, et al. DNA damage repair deficiency as a predictive biomarker for FOLFIRINOX efficacy in metastatic pancreatic cancer. J Gastrointest Oncol. 2019;10:1133–9.

    PubMed  PubMed Central  Article  Google Scholar 

  150. 150.

    Litton JK, Rugo HS, Ettl J, Hurvitz SA, Goncalves A, Lee KH, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379:753–63.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  151. 151.

    Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495–505.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  152. 152.

    Mateo J, Porta N, Bianchini D, McGovern U, Elliott T, Jones R, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21:162–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. 153.

    Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016;16:110–20.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  154. 154.

    Nanda N, Roberts NJ. ATM serine/threonine kinase and its role in pancreatic risk. Genes (Basel). 2020;11:108.

  155. 155.

    Hu C, Hart SN, Polley EC, Gnanaolivu R, Shimelis H, Lee KY, et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA. 2018;319:2401–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    Roberts NJ, Jiao Y, Yu J, Kopelovich L, Petersen GM, Bondy ML, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;2:41–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  157. 157.

    Kim H, Saka B, Knight S, Borges M, Childs E, Klein A, et al. Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis. Clin Cancer Res. 2014;20:1865–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158.

    Kamphues C, Bova R, Bahra M, Klauschen F, Muckenhuber A, Sinn BV, et al. Ataxia-telangiectasia-mutated protein kinase levels stratify patients with pancreatic adenocarcinoma into prognostic subgroups with loss being a strong indicator of poor survival. Pancreas. 2015;44:296–301.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  159. 159.

    Golan T, Sella T, O’Reilly EM, Katz MHG, Epelbaum R, Kelsen DP, et al. Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer. Br J Cancer. 2017;116:697–702.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. 160.

    Perkhofer L, Schmitt A, Romero Carrasco MC, Ihle M, Hampp S, Ruess DA, et al. ATM deficiency generating genomic instability sensitizes pancreatic ductal adenocarcinoma cells to therapy-induced DNA damage. Cancer Res. 2017;77:5576–90.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  161. 161.

    Choi M, Kipps T, Kurzrock R. ATM mutations in cancer: therapeutic implications. Mol Cancer Ther. 2016;15:1781–91.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  162. 162.

    Smith J, Tho LM, Xu N, Gillespie DA. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res. 2010;108:73–112.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  163. 163.

    Armstrong SA, Schultz CW, Azimi-Sadjadi A, Brody JR, Pishvaian MJ. ATM dysfunction in pancreatic adenocarcinoma and associated therapeutic implications. Mol Cancer Ther. 2019;18:1899–908.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  164. 164.

    Kawamura D, Takemoto Y, Nishimoto A, Ueno K, Hosoyama T, Shirasawa B, et al. Enhancement of cytotoxic effects of gemcitabine by Dclk1 inhibition through suppression of Chk1 phosphorylation in human pancreatic cancer cells. Oncol Rep. 2017;38:3238–44.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  165. 165.

    Duong HQ, Hong YB, Kim JS, Lee HS, Yi YW, Kim YJ, et al. Inhibition of checkpoint kinase 2 (CHK2) enhances sensitivity of pancreatic adenocarcinoma cells to gemcitabine. J Cell Mol Med. 2013;17:1261–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. 166.

    Heeke AL, Pishvaian MJ, Lynce F, Xiu J, Brody JR, Chen WJ, et al. Prevalence of homologous recombination-related gene mutations across multiple cancer types. JCO Precis Oncol. 2018;2018:1–13.

    Google Scholar 

  167. 167.

    Nepomuceno TC, De Gregoriis G, de Oliveira FMB, Suarez-Kurtz G, Monteiro AN, Carvalho MA. The role of PALB2 in the DNA damage response and cancer predisposition. Int J Mol Sci. 2017;18:1886.

    PubMed Central  Article  CAS  Google Scholar 

  168. 168.

    Zhen DB, Rabe KG, Gallinger S, Syngal S, Schwartz AG, Goggins MG, et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med. 2015;17:569–77.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  169. 169.

    Harinck F, Kluijt I, van Mil SE, Waisfisz Q, van Os TA, Aalfs CM, et al. Routine testing for PALB2 mutations in familial pancreatic cancer families and breast cancer families with pancreatic cancer is not indicated. Eur J Hum Genet. 2012;20:577–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  170. 170.

    Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Parsons DW, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324:217.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. 171.

    Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkas K, Roberts J, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371:497–506.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  172. 172.

    Hu C, LaDuca H, Shimelis H, Polley EC, Lilyquist J, Hart SN, et al. Multigene hereditary cancer panels reveal high-risk pancreatic cancer susceptibility genes. JCO Precis Oncol. 2018;2:PO.17.00291.

    PubMed Central  Google Scholar 

  173. 173.

    Villarroel MC, Rajeshkumar NV, Garrido-Laguna I, De Jesus-Acosta A, Jones S, Maitra A, et al. Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. Mol Cancer Ther. 2011;10:3–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  174. 174.

    Park D, Shakya R, Koivisto C, Pitarresi JR, Szabolcs M, Kladney R, et al. Murine models for familial pancreatic cancer: histopathology, latency and drug sensitivity among cancers of Palb2, Brca1 and Brca2 mutant mouse strains. PLoS One. 2019;14:e0226714.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. 175.

    de Bono J, Ramanathan RK, Mina L, Chugh R, Glaspy J, Rafii S, et al. Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discov. 2017;7:620–9.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  176. 176.

    Perez-Mancera PA, Guerra C, Barbacid M, Tuveson DA. What we have learned about pancreatic cancer from mouse models. Gastroenterology. 2012;142:1079–92.

    PubMed  Article  PubMed Central  Google Scholar 

  177. 177.

    Davis EJ, Johnson DB, Sosman JA, Chandra S. Melanoma: what do all the mutations mean? Cancer-Am Cancer Soc. 2018;124:3490–9.

    Google Scholar 

  178. 178.

    Collisson EA, Trejo CL, Silva JM, Gu S, Korkola JE, Heiser LM, et al. A central role for RAF->MEK->ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov. 2012;2:685–93.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. 179.

    Witkiewicz AK, McMillan EA, Balaji U, Baek G, Lin WC, Mansour J, et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun. 2015;6:6744.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. 180.

    Foster SA, Whalen DM, Ozen A, Wongchenko MJ, Yin J, Yen I, et al. Activation mechanism of oncogenic deletion mutations in BRAF, EGFR, and HER2. Cancer Cell. 2016;29:477–93.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  181. 181.

    Zhang W. BRAF inhibitors: the current and the future. Curr Opin Pharmacol. 2015;23:68–73.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  182. 182.

    Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877–88.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  183. 183.

    Long GV, Hauschild A, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  184. 184.

    Wrzeszczynski KO, Rahman S, Frank MO, Arora K, Shah M, Geiger H, et al. Identification of targetable BRAF DeltaN486_P490 variant by whole-genome sequencing leading to dabrafenib-induced remission of a BRAF-mutant pancreatic adenocarcinoma. Cold Spring Harb Mol Case Stud. 2019;5.

  185. 185.

    DuFort CC, DelGiorno KE, Hingorani SR. Mounting pressure in the microenvironment: fluids, solids, and cells in pancreatic ductal adenocarcinoma. Gastroenterology. 2016;150:1545–57 e2.

    PubMed  PubMed Central  Article  Google Scholar 

  186. 186.

    Mahadevan D, Von Hoff DD. Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 2007;6:1186–97.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  187. 187.

    Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:418–29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  188. 188.

    Baker LA, Tiriac H, Clevers H, Tuveson DA. Modeling pancreatic cancer with organoids. Trends Cancer. 2016;2:176–90.

    PubMed  PubMed Central  Article  Google Scholar 

  189. 189.

    Kim J, Koo BK, Knoblich JA. Human organoids: model systems for human biology and medicine. Nat Rev Mol Cell Biol. 2020;21:571–84.

  190. 190.

    Tiriac H, Belleau P, Engle DD, Plenker D, Deschenes A, Somerville TDD, et al. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer. Cancer Discov. 2018;8:1112–29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  191. 191.

    Boj SF, Hwang CI, Baker LA, Chio II, Engle DD, Corbo V, et al. Organoid models of human and mouse ductal pancreatic cancer. Cell. 2015;160:324–38.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  192. 192.

    Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu SD, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011;17:500–U140.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  193. 193.

    Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. 194.

    O’Reilly EM, Hechtman JF. Tumour response to TRK inhibition in a patient with pancreatic adenocarcinoma harbouring an NTRK gene fusion. Ann Oncol. 2019;30:Viii36–i40.

    PubMed  PubMed Central  Article  Google Scholar 

  195. 195.

    Hayashi H, Tanishima S, Fujii K, Mori R, Okamura Y, Yanagita E, et al. Genomic testing for pancreatic cancer in clinical practice as real-world evidence. Pancreatology. 2018;18:647–54.

    PubMed  Article  PubMed Central  Google Scholar 

  196. 196.

    Lowery MA, Jordan EJ, Basturk O, Ptashkin RN, Zehir A, Berger MF, et al. Real-time genomic profiling of pancreatic ductal adenocarcinoma: potential actionability and correlation with clinical phenotype. Clin Cancer Res. 2017;23:6094–100.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  197. 197.

    Chantrill LA, Nagrial AM, Watson C, Johns AL, Martyn-Smith M, Simpson S, et al. Precision medicine for advanced pancreas cancer: the individualized molecular pancreatic cancer therapy (IMPaCT) trial. Clin Cancer Res. 2015;21:2029–37.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  198. 198.

    Shi S, Liang C, Xu J, Meng Q, Hua J, Yang X, et al. The strain ratio as obtained by endoscopic ultrasonography elastography correlates with the stroma proportion and the prognosis of local pancreatic cancer. Ann Surg. 2020;271:559–65.

    PubMed  Article  PubMed Central  Google Scholar 

  199. 199.

    Chung V, McDonough S, Philip PA, Cardin D, Wang-Gillam A, Hui L, et al. Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial. JAMA Oncol. 2017;3:516–22.

    PubMed  PubMed Central  Article  Google Scholar 

  200. 200.

    Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C. Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer. 2008;8:82.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  201. 201.

    Weden S, Klemp M, Gladhaug IP, Moller M, Eriksen JA, Gaudernack G, et al. Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. Int J Cancer. 2011;128:1120–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  202. 202.

    Van Cutsem E, Hidalgo M, Canon JL, Macarulla T, Bazin I, Poddubskaya E, et al. Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer. Int J Cancer. 2018;143:2053–64.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  203. 203.

    Ko AH, Bekaii-Saab T, Van Ziffle J, Mirzoeva OM, Joseph NM, Talasaz A, et al. A multicenter, open-label phase II clinical trial of combined MEK plus EGFR inhibition for chemotherapy-refractory advanced pancreatic adenocarcinoma. Clin Cancer Res. 2016;22:61–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  204. 204.

    Infante JR, Somer BG, Park JO, Li CP, Scheulen ME, Kasubhai SM, et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur J Cancer. 2014;50:2072–81.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  205. 205.

    Bodoky G, Timcheva C, Spigel DR, La Stella PJ, Ciuleanu TE, Pover G. et al. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs. 2012;30:1216–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  206. 206.

    Van Laethem JL, Riess H, Jassem J, Haas M, Martens UM, Weekes C, et al. Phase I/II study of refametinib (BAY 86-9766) in combination with gemcitabine in advanced pancreatic cancer. Target Oncol. 2017;12:97–109.

    PubMed  Article  PubMed Central  Google Scholar 

  207. 207.

    Rinehart J, Adjei AA, Lorusso PM, Waterhouse D, Hecht JR, Natale RB, et al. Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol. 2004;22:4456–62.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  208. 208.

    Karavasilis V, Samantas E, Koliou GA, Kalogera-Fountzila A, Pentheroudakis G, Varthalitis I, et al. Gemcitabine combined with the mTOR inhibitor temsirolimus in patients with locally advanced or metastatic pancreatic cancer. a hellenic cooperative oncology group phase I/II study. Target Oncol. 2018;13:715–24.

    PubMed  Article  PubMed Central  Google Scholar 

  209. 209.

    Kordes S, Klumpen HJ, Weterman MJ, Schellens JH, Richel DJ, Wilmink JW. Phase II study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced pancreatic cancer. Cancer Chemother Pharmacol. 2015;75:1135–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  210. 210.

    Kordes S, Richel DJ, Klumpen HJ, Weterman MJ, Stevens AJ, Wilmink JW. A phase I/II, non-randomized, feasibility/safety and efficacy study of the combination of everolimus, cetuximab and capecitabine in patients with advanced pancreatic cancer. Invest New Drugs. 2013;31:85–91.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  211. 211.

    Wolpin BM, Hezel AF, Abrams T, Blaszkowsky LS, Meyerhardt JA, Chan JA, et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol. 2009;27:193–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  212. 212.

    Javle MM, Shroff RT, Xiong H, Varadhachary GA, Fogelman D, Reddy SA, et al. Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies. BMC Cancer. 2010;10:368.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  213. 213.

    O’Neil BH, Scott AJ, Ma WW, Cohen SJ, Aisner DL, Menter AR, et al. A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer. Ann Oncol. 2016;27:1180.

    PubMed  PubMed Central  Article  Google Scholar 

  214. 214.

    Makielski RJ, Lubner SJ, Mulkerin DL, Traynor AM, Groteluschen D, Eickhoff J, et al. A phase II study of sorafenib, oxaliplatin, and 2 days of high-dose capecitabine in advanced pancreas cancer. Cancer Chemother Pharmacol. 2015;76:317–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  215. 215.

    Goncalves A, Gilabert M, Francois E, Dahan L, Perrier H, Lamy R, et al. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol. 2012;23:2799–805.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  216. 216.

    El-Khoueiry AB, Ramanathan RK, Yang DY, Zhang W, Shibata S, Wright JJ, et al. A randomized phase II of gemcitabine and sorafenib versus sorafenib alone in patients with metastatic pancreatic cancer. Invest New Drugs. 2012;30:1175–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  217. 217.

    Cardin DB, Goff L, Li CI, Shyr Y, Winkler C, DeVore R, et al. Phase II trial of sorafenib and erlotinib in advanced pancreatic cancer. Cancer Med. 2014;3:572–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  218. 218.

    Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007;25:1960–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  219. 219.

    Tjensvoll K, Lapin M, Buhl T, Oltedal S, Steen-Ottosen Berry K, Gilje B, et al. Clinical relevance of circulating KRAS mutated DNA in plasma from patients with advanced pancreatic cancer. Mol Oncol. 2016;10:635–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  220. 220.

    Nakano Y, Kitago M, Matsuda S, Nakamura Y, Fujita Y, Imai S, et al. KRAS mutations in cell-free DNA from preoperative and postoperative sera as a pancreatic cancer marker: a retrospective study. Br J Cancer. 2018;118:662–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  221. 221.

    Temraz S, Shamseddine A, Mukherji D, Charafeddine M, Tfayli A, Assi H, et al. Ki67 and P53 in relation to disease progression in metastatic pancreatic cancer: a single institution analysis. Pathol Oncol Res. 2019;25:1059–66.

    PubMed  Article  PubMed Central  Google Scholar 

  222. 222.

    Tascilar M, Skinner HG, Rosty C, Sohn T, Wilentz RE, Offerhaus GJ, et al. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2001;7:4115–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  223. 223.

    Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15:2403–13.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  224. 224.

    Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2009;27:5513–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  225. 225.

    Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, et al. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016;388:248–57.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  226. 226.

    Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379:2395–406.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057), National Science Foundation for Distinguished Young Scholars of China [81625016], National Natural Science Foundation of China (No. 81871950 and 81972250), Shanghai Municipal Commission of Health and Family Planning (No. 2018YQ06).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Qi-feng Zhuo or Shun-rong Ji.

Ethics declarations

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hu, Hf., Ye, Z., Qin, Y. et al. Mutations in key driver genes of pancreatic cancer: molecularly targeted therapies and other clinical implications. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-020-00584-2

Download citation

Keywords

  • pancreatic cancer
  • KRAS
  • CDKN2A
  • TP53
  • SMAD4
  • clinical implication

Search

Quick links