Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second most common cause of death within the next 10 years. The prognosis for this disease is poor despite diagnostic progress and new chemotherapeutic regimens. The oncogenic KRAS mutation is the major event in pancreatic cancer; it confers permanent activation of the KRAS protein, which acts as a molecular switch to activate various intracellular signalling pathways and transcription factors inducing cell proliferation, migration, transformation and survival. Several laboratory methods have been developed to detect KRAS mutations in biological samples, including digital droplet PCR (which displays high sensitivity). Clinical studies have revealed that a KRAS mutation assay in fine-needle aspiration material combined with cytopathology increases the sensitivity, accuracy and negative predictive value of cytopathology for a positive diagnosis of pancreatic cancer. In addition, the presence of KRAS mutations in serum and plasma (liquid biopsies) correlates with a worse prognosis. The presence of mutated KRAS can also have therapeutic implications, whether at the gene level per se, during its post-translational maturation, interaction with nucleotides and after activation of the various oncogenic signals. Further pharmacokinetic and toxicological studies on new molecules are required, especially small synthetic molecules, before they can be used in the therapeutic arsenal for pancreatic ductal adenocarcinoma.
The major genetic event in pancreatic ductal adenocarcinoma is the activating point mutation of the KRAS oncogene; the KRAS protein becomes permanently activated, consequently maintaining the cellular processes of proliferation, transformation, invasion and survival.
Detection of KRAS mutations can be performed in a variety of biological samples including fresh and fixed tumour tissue or biopsy samples, fine-needle aspiration materials and cytological samples, and in total blood and plasma.
The KRAS mutation assay can be combined with endoscopic ultrasonography-guided cytopathology to increase the sensitivity, the negative predictive value and accuracy of cytopathology alone for the positive diagnosis of pancreatic cancer and its differential diagnosis with chronic pancreatitis.
The presence of mutated KRAS correlates with a worse prognosis for patients with pancreatic cancer whether or not they undergo curative surgery. KRAS mutation assays could provide important predictive information on tumour progression and recurrence.
Mutated KRAS might be targeted therapeutically, especially at the gene level and during its post-translational maturation; the interactions between KRAS proteins and adaptor proteins or nucleotides and downstream oncogenic signals might also be targeted.
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Rahib, L. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921 (2014).
Are, C. et al. Predictive global trends in the incidence and mortality of pancreatic cancer based on geographic location, socio-economic status, and demographic shift. J. Surg. Oncol. 114, 736–742 (2016).
Bouvier, A.-M. et al. Focus on an unusual rise in pancreatic cancer incidence in France. Int. J. Epidemiol 46, 1764–1772 (2017).
Ryan, D. P., Hong, T. S. & Bardeesy, N. Pancreatic adenocarcinoma. N. Engl. J. Med. 371, 1039–1049 (2014).
Ducreux, M., Boige, V. & Malka, D. Treatment of advanced pancreatic cancer. Semin. Oncol. 34, S25–S30 (2007).
Neoptolemos, J. P. et al. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat. Rev. Gastroenterol. Hepatol. 15, 333–348 (2018).
Conroy, T. et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N. Engl. J. Med. 379, 2395–2406 (2018).
Klemm, F. & Joyce, J. A. Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol. 25, 198–213 (2015).
Bijlsma, M. F., Sadanandam, A., Tan, P. & Vermeulen, L. Molecular subtypes in cancers of the gastrointestinal tract. Nat. Rev. Gastroenterol. Hepatol. 14, 333–342 (2017).
Witkiewicz, A. K. et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat. Commun. 6, 6744 (2015).
Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).
Puleo, F. et al. Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features. Gastroenterology 155, 1999–2013.e3 (2018).
Delpu, Y. et al. Genetic and epigenetic alterations in pancreatic carcinogenesis. Curr. Genomics 12, 15–24 (2011).
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 54, 75–83 (2016).
Haigis, K. M. KRAS alleles: the devil is in the detail. Trends Cancer 3, 686–697 (2017).
Sinicrope, F. A., Okamoto, K., Kasi, P. M. & Kawakami, H. Molecular biomarkers in the personalized treatment of colorectal cancer. Clin. Gastroenterol. Hepatol. 14, 651–658 (2016).
Lindsay, C. R., Jamal-Hanjani, M., Forster, M. & Blackhall, F. KRAS: reasons for optimism in lung cancer. Eur. J. Cancer 99, 20–27 (2018).
Fuccio, L. et al. The role of K-ras gene mutation analysis in EUS-guided FNA cytology specimens for the differential diagnosis of pancreatic solid masses: a meta-analysis of prospective studies. Gastrointest. Endosc. 78, 596–608 (2013).
di Magliano, M. P. & Logsdon, C. D. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology 144, 1220–1229 (2013).
Zeitouni, D., Pylayeva-Gupta, Y., Der, C. J. & Bryant, K. L. KRAS mutant pancreatic cancer: no lone path to an effective treatment. Cancers 8, E45 (2016).
Cox, A. D., Der, C. J. & Philips, M. R. Targeting RAS membrane association: back to the future for anti-RAS drug discovery? Clin. Cancer Res. 21, 1819–1827 (2015).
Jonckheere, N., Vasseur, R. & Van Seuningen, I. The cornerstone K-RAS mutation in pancreatic adenocarcinoma: from cell signaling network, target genes, biological processes to therapeutic targeting. Crit. Rev. Oncol. Hematol. 111, 7–19 (2017).
Löhr, M., Klöppel, G., Maisonneuve, P., Lowenfels, A. B. & Lüttges, J. Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis. Neoplasia 7, 17–23 (2005).
Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).
Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).
Bardeesy, N. et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 20, 3130–3146 (2006).
Bardeesy, N. et al. Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc. Natl Acad. Sci. USA 103, 5947–5952 (2006).
Siveke, J. T. et al. Concomitant pancreatic activation of Kras(G12D) and Tgfa results in cystic papillary neoplasms reminiscent of human IPMN. Cancer Cell 12, 266–279 (2007).
Aguirre, A. J. et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112–3126 (2003).
Izeradjene, K. et al. Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 11, 229–243 (2007).
Guerra, C. & Barbacid, M. Genetically engineered mouse models of pancreatic adenocarcinoma. Mol. Oncol 7, 232–247 (2013).
Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).
Guerra, C. et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728–739 (2011).
Pinho, A. V., Chantrill, L. & Rooman, I. Chronic pancreatitis: a path to pancreatic cancer. Cancer Lett. 345, 203–209 (2014).
Ardito, C. M. et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22, 304–317 (2012).
Navas, C. et al. EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 22, 318–330 (2012).
Chiou, S.-H. et al. Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing. Genes Dev. 29, 1576–1585 (2015).
Maresch, R. et al. Multiplexed pancreatic genome engineering and cancer induction by transfection-based CRISPR/Cas9 delivery in mice. Nat. Commun. 7, 10770 (2016).
Bailey, J. M. et al. p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells. Oncogene 35, 4282–4288 (2016).
Lee, A. Y. L. et al. Cell of origin affects tumour development and phenotype in pancreatic ductal adenocarcinoma. Gut 68, 487–498 (2019).
Gidekel Friedlander, S. Y. et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16, 379–389 (2009).
Mueller, S. et al. Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature 554, 62–68 (2018).
Collins, M. A. et al. Metastatic pancreatic cancer is dependent on oncogenic Kras in mice. PLOS ONE 7, e49707 (2012).
Collins, M. A. et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J. Clin. Invest. 122, 639–653 (2012).
Huang, L. et al. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Nat. Med. 21, 1364–1371 (2015).
Tiriac, H., Plenker, D., Baker, L. A. & Tuveson, D. A. Organoid models for translational pancreatic cancer research. Curr. Opin. Genet. Dev. 54, 7–11 (2019).
Perera, R. M. & Bardeesy, N. Pancreatic cancer metabolism: breaking it down to build it back up. Cancer Discov. 5, 1247–1261 (2015).
Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013).
Tape, C. J. et al. Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell 165, 910–920 (2016).
Zhang, W. et al. Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma. Sci. Signal. 7, ra42 (2014).
Lesina, M. et al. Stat3/Socs3 activation by IL-6 trans-signaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19, 456–469 (2011).
Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G. & Bar-Sagi, D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21, 836–847 (2012).
Clark, C. E. et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 67, 9518–9527 (2007).
Zhang, Y. et al. Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer. Gut 66, 124–136 (2017).
Matsuo, Y. et al. K-Ras promotes angiogenesis mediated by immortalized human pancreatic epithelial cells through mitogen-activated protein kinase signaling pathways. Mol. Cancer Res. 7, 799–808 (2009).
Mann, K. M., Ying, H., Juan, J., Jenkins, N. A. & Copeland, N. G. KRAS-related proteins in pancreatic cancer. Pharmacol. Ther. 168, 29–42 (2016).
Collins, M. A., Yan, W., Sebolt-Leopold, J. S. & Pasca di Magliano, M. MAPK signaling is required for dedifferentiation of acinar cells and development of pancreatic intraepithelial neoplasia in mice. Gastroenterology 146, 822–834.e7 (2014).
Shin, S. Y., Choi, C., Lee, H. G., Lim, Y. & Lee, Y. H. Transcriptional regulation of the interleukin-11 gene by oncogenic Ras. Carcinogenesis 33, 2467–2476 (2012).
Zheng, C., Jiao, X., Jiang, Y. & Sun, S. ERK1/2 activity contributes to gemcitabine resistance in pancreatic cancer cells. J. Int. Med. Res. 41, 300–306 (2013).
Baer, R., Cintas, C., Therville, N. & Guillermet-Guibert, J. Implication of PI3K/Akt pathway in pancreatic cancer: when PI3K isoforms matter? Adv. Biol. Regul. 59, 19–35 (2015).
Prabhu, L., Mundade, R., Korc, M., Loehrer, P. J. & Lu, T. Critical role of NF-κB in pancreatic cancer. Oncotarget 5, 10969–10975 (2014).
Seguin, L. et al. An integrin β3-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat. Cell Biol. 16, 457–468 (2014).
Miller, M. S. & Miller, L. D. RAS mutations and oncogenesis: not all RAS mutations are created equally. Front. Genet. 2, 100 (2011).
Ihle, N. T. et al. Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J. Natl Cancer Inst. 104, 228–239 (2012).
Hunter, J. C. et al. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol. Cancer Res. 13, 1325–1335 (2015).
Pantsar, T. et al. Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling. PLOS Comput. Biol. 14, e1006458 (2018).
Zhang, L., Sanagapalli, S. & Stoita, A. Challenges in diagnosis of pancreatic cancer. World J. Gastroenterol. 24, 2047–2060 (2018).
Costello, E., Greenhalf, W. & Neoptolemos, J. P. New biomarkers and targets in pancreatic cancer and their application to treatment. Nat. Rev. Gastroenterol. Hepatol. 9, 435–444 (2012).
Buscail, L., Faure, P., Bournet, B., Selves, J. & Escourrou, J. Interventional endoscopic ultrasound in pancreatic diseases. Pancreatology 6, 7–16 (2006).
Kamata, K. et al. Impact of avascular areas, as measured by contrast-enhanced harmonic EUS, on the accuracy of FNA for pancreatic adenocarcinoma. Gastrointest. Endosc. 87, 158–163 (2018).
Hewitt, M. J. et al. EUS-guided FNA for diagnosis of solid pancreatic neoplasms: a meta-analysis. Gastrointest. Endosc. 75, 319–331 (2012).
Savides, T. J. et al. EUS-guided FNA diagnostic yield of malignancy in solid pancreatic masses: a benchmark for quality performance measurement. Gastrointest. Endosc. 66, 277–282 (2007).
Yoshinaga, S., Suzuki, H., Oda, I. & Saito, Y. Role of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for diagnosis of solid pancreatic masses. Dig. Endosc. 23 (Suppl 1), 29–33 (2011).
Sanjeevi, S. et al. Impact of delay between imaging and treatment in patients with potentially curable pancreatic cancer. Br. J. Surg. 103, 267–275 (2016).
Swords, D. S., Firpo, M. A., Scaife, C. L. & Mulvihill, S. J. Biomarkers in pancreatic adenocarcinoma: current perspectives. Onco Targets Ther. 9, 7459–7467 (2016).
Imamura, T. et al. Liquid biopsy in patients with pancreatic cancer: circulating tumor cells and cell-free nucleic acids. World J. Gastroenterol. 22, 5627–5641 (2016).
Zhang, R. et al. Synthetic circulating cell-free DNA as quality control materials for somatic mutation detection in liquid biopsy for cancer. Clin. Chem. 63, 1465–1475 (2017).
Riva, F. et al. Clinical applications of circulating tumor DNA and circulating tumor cells in pancreatic cancer. Mol. Oncol. 10, 481–493 (2016).
Bernard, V. et al. Circulating nucleic acids are associated with outcomes of patients with pancreatic cancer. Gastroenterology 156, 108–118.e4 (2019).
Earl, J. et al. Circulating tumor cells (Ctc) and kras mutant circulating free Dna (cfdna) detection in peripheral blood as biomarkers in patients diagnosed with exocrine pancreatic cancer. BMC Cancer 15, 797 (2015).
Isler, J. A., Vesterqvist, O. E. & Burczynski, M. E. Analytical validation of genotyping assays in the biomarker laboratory. Pharmacogenomics 8, 353–368 (2007).
Fariña Sarasqueta, A. et al. SNaPshot and StripAssay as valuable alternatives to direct sequencing for KRAS mutation detection in colon cancer routine diagnostics. J. Mol. Diagn. 13, 199–205 (2011).
Shackelford, R. E., Whitling, N. A., McNab, P., Japa, S. & Coppola, D. KRAS testing: a tool for the implementation of personalized medicine. Genes Cancer 3, 459–466 (2012).
Liu, Y., Gudnason, H., Li, Y.-P., Bang, D. D. & Wolff, A. An oligonucleotide-tagged microarray for routine diagnostics of colon cancer by genotyping KRAS mutations. Int. J. Oncol. 45, 1556–1564 (2014).
Lin, M.-T. et al. Clinical validation of KRAS, BRAF, and EGFR mutation detection using next-generation sequencing. Am. J. Clin. Pathol. 141, 856–866 (2014).
Oh, J. E. et al. Detection of low-level KRAS mutations using PNA-mediated asymmetric PCR clamping and melting curve analysis with unlabeled probes. J. Mol. Diagn. 12, 418–424 (2010).
Linardou, H. et al. All about KRAS for clinical oncology practice: gene profile, clinical implications and laboratory recommendations for somatic mutational testing in colorectal cancer. Cancer Treat. Rev. 37, 221–233 (2011).
Zuo, Z. et al. Application of COLD-PCR for improved detection of KRAS mutations in clinical samples. Mod. Pathol. 22, 1023–1031 (2009).
How Kit, A. et al. Sensitive detection of KRAS mutations using enhanced-ice-COLD-PCR mutation enrichment and direct sequence identification. Hum. Mutat. 34, 1568–1580 (2013).
Azuara, D. et al. Nanofluidic digital PCR for KRAS mutation detection and quantification in gastrointestinal cancer. Clin. Chem. 58, 1332–1341 (2012).
Taly, V. et al. Multiplex picodroplet digital PCR to detect KRAS mutations in circulating DNA from the plasma of colorectal cancer patients. Clin. Chem. 59, 1722–1731 (2013).
Dong, L., Wang, S., Fu, B. & Wang, J. Evaluation of droplet digital PCR and next generation sequencing for characterizing DNA reference material for KRAS mutation detection. Sci. Rep. 8, 9650 (2018).
Bournet, B. et al. Endoscopic ultrasound-guided fine-needle aspiration biopsy coupled with a KRAS mutation assay using allelic discrimination improves the diagnosis of pancreatic cancer. J. Clin. Gastroenterol. 49, 50–56 (2015).
Bournet, B. et al. Endoscopic ultrasound-guided fine-needle aspiration biopsy coupled with KRAS mutation assay to distinguish pancreatic cancer from pseudotumoral chronic pancreatitis. Endoscopy 41, 552–557 (2009).
Anderson, S. M. Laboratory methods for KRAS mutation analysis. Expert Rev. Mol. Diagn. 11, 635–642 (2011).
Pritchard, C. C., Akagi, L., Reddy, P. L., Joseph, L. & Tait, J. F. COLD-PCR enhanced melting curve analysis improves diagnostic accuracy for KRAS mutations in colorectal carcinoma. BMC Clin. Pathol. 10, 6 (2010).
Oliner, K. et al. A comparability study of 5 commercial KRAS tests. Diagn. Pathol. 5, 23 (2010).
De Roock, W. et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 304, 1812–1820 (2010).
Boulaiz, H. et al. What’s new in the diagnosis of pancreatic cancer: a patent review (2011–present). Expert Opin. Ther. Pat. 27, 1319–1328 (2017).
Sho, S. et al. Digital PCR improves mutation analysis in pancreas fine needle aspiration biopsy specimens. PLOS ONE 12, e0170897 (2017).
Pellisé, M. et al. Clinical usefulness of KRAS mutational analysis in the diagnosis of pancreatic adenocarcinoma by means of endosonography-guided fine-needle aspiration biopsy. Aliment. Pharmacol. Ther. 17, 1299–1307 (2003).
Takahashi, K. et al. Differential diagnosis of pancreatic cancer and focal pancreatitis by using EUS-guided FNA. Gastrointest. Endosc. 61, 76–79 (2005).
Maluf-Filho, F. et al. Kras mutation analysis of fine needle aspirate under EUS guidance facilitates risk stratification of patients with pancreatic mass. J. Clin. Gastroenterol. 41, 906–910 (2007).
Reicher, S. et al. Fluorescence in situ hybridization and K-ras analyses improve diagnostic yield of endoscopic ultrasound-guided fine-needle aspiration of solid pancreatic masses. Pancreas 40, 1057–1062 (2011).
Ogura, T. et al. Clinical impact of K-ras mutation analysis in EUS-guided FNA specimens from pancreatic masses. Gastrointest. Endosc. 75, 769–774 (2012).
Ginestà, M. M. et al. Genetic and epigenetic markers in the evaluation of pancreatic masses. J. Clin. Pathol. 66, 192–197 (2013).
Matsubayashi, H. Role of K-ras mutation analysis in EUS-FNA samples obtained from pancreatic solid mass. J. Clin. Gastroenterol. 49, 173 (2015).
Trisolini, E. et al. KRAS mutation testing on all non-malignant diagnosis of pancreatic endoscopic ultrasound-guided fine-needle aspiration biopsies improves diagnostic accuracy. Pathology 49, 379–386 (2017).
Sekita-Hatakeyama, Y. et al. K-ras mutation analysis of residual liquid-based cytology specimens from endoscopic ultrasound-guided fine needle aspiration improves cell block diagnosis of pancreatic ductal adenocarcinoma. PLOS ONE 13, e0193692 (2018).
Khalid, A. et al. EUS-FNA mutational analysis in differentiating autoimmune pancreatitis and pancreatic cancer. Pancreatology 11, 482–486 (2011).
Mandel, P. & Metais, P. Les acides nucleiques du plasma sanguin chez l’homme [French]. C. R. Seances Soc. Biol. Fil. 142, 241–243 (1948).
Bendich, A., Wilczok, T. & Borenfreund, E. Circulation DNA as a possible factor in oncogenesis. Science 148, 374–376 (1965).
Diaz, L. A. & Bardelli, A. Liquid biopsies: genotyping circulating tumor DNA. J. Clin. Oncol. 32, 579–586 (2014).
Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).
Diehl, F. et al. Circulating mutant DNA to assess tumor dynamics. Nat. Med. 14, 985–990 (2008).
Buscail, E. et al. Tumor-proximal liquid biopsy to improve diagnostic and prognostic performances of circulating tumor cells. Mol. Oncol. 13, 1811–1826 (2019).
Chemi, F. et al. Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse. Nat. Med. 25, 1534–1539 (2019).
Wei, T. et al. Monitoring tumor burden in response to FOLFIRINOX chemotherapy via profiling circulating cell-free DNA in pancreatic cancer. Mol. Cancer Ther. 18, 196–203 (2019).
Sausen, M. et al. Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients. Nat. Commun. 6, 7686 (2015).
Brychta, N., Krahn, T. & von Ahsen, O. Detection of KRAS mutations in circulating tumor DNA by digital PCR in early stages of pancreatic cancer. Clin. Chem. 62, 1482–1491 (2016).
Park, G. et al. Utility of targeted deep sequencing for detecting circulating tumor DNA in pancreatic cancer patients. Sci. Rep. 8, 11631 (2018).
Cohen, J. D. et al. Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers. Proc. Natl Acad. Sci. USA 114, 10202–10207 (2017).
Buscail, E. et al. Liquid biopsy approach for pancreatic ductal adenocarcinoma. Cancers 11, 852 (2019).
Andriamanampisoa, C.-L. et al. BIABooster: online DNA concentration and size profiling with a limit of detection of 10 fg/μL and application to high-sensitivity characterization of circulating cell-free DNA. Anal. Chem. 90, 3766–3774 (2018).
Cacheux, J., Brut, M., Bancaud, A., Cordelier, P. & Leïchlé, T. Spatial analysis of nanofluidic-embedded biosensors for wash-free single-nucleotide difference discrimination. ACS Sens. 3, 606–611 (2018).
Däbritz, J., Preston, R., Hänfler, J. & Oettle, H. Follow-up study of K-ras mutations in the plasma of patients with pancreatic cancer: correlation with clinical features and carbohydrate antigen 19-9. Pancreas 38, 534–541 (2009).
Chen, H. et al. K-ras mutational status predicts poor prognosis in unresectable pancreatic cancer. Eur. J. Surg. Oncol. 36, 657–662 (2010).
Singh, N., Gupta, S., Pandey, R. M., Chauhan, S. S. & Saraya, A. High levels of cell-free circulating nucleic acids in pancreatic cancer are associated with vascular encasement, metastasis and poor survival. Cancer Invest. 33, 78–85 (2015).
Kinugasa, H. et al. Detection of K-ras gene mutation by liquid biopsy in patients with pancreatic cancer. Cancer 121, 2271–2280 (2015).
Takai, E. et al. Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer. Sci. Rep. 5, 18425 (2015).
Hadano, N. et al. Prognostic value of circulating tumour DNA in patients undergoing curative resection for pancreatic cancer. Br. J. Cancer 115, 59–65 (2016).
Cheng, H. et al. Analysis of ctDNA to predict prognosis and monitor treatment responses in metastatic pancreatic cancer patients. Int. J. Cancer 140, 2344–2350 (2017).
Pietrasz, D. et al. Plasma circulating tumor DNA in pancreatic cancer patients is a prognostic marker. Clin. Cancer Res. 23, 116–123 (2017).
Van Laethem, J.-L. et al. Phase I/II study of refametinib (BAY 86-9766) in combination with gemcitabine in advanced pancreatic cancer. Target. Oncol. 12, 97–109 (2017).
Allenson, K. et al. High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients. Ann. Oncol. 28, 741–747 (2017).
Kim, M. K. et al. Prognostic implications of multiplex detection of KRAS mutations in cell-free DNA from patients with pancreatic ductal adenocarcinoma. Clin. Chem. 64, 726–734 (2018).
Lin, M. et al. Circulating tumor DNA as a sensitive marker in patients undergoing irreversible electroporation for pancreatic cancer. Cell Physiol. Biochem. 47, 1556–1564 (2018).
Lee, B. et al. Circulating tumor DNA as a potential marker of adjuvant chemotherapy benefit following surgery for localised pancreatic cancer. Ann. Oncol. 30, 1472–1478 (2019).
Kawesha, A. et al. K-ras oncogene subtype mutations are associated with survival but not expression of p53, p16(INK4A), p21(WAF-1), cyclin D1, erbB-2 and erbB-3 in resected pancreatic ductal adenocarcinoma. Int. J. Cancer 89, 469–474 (2000).
Niedergethmann, M. et al. Prognostic implications of routine, immunohistochemical, and molecular staging in resectable pancreatic adenocarcinoma. Am. J. Surg. Pathol. 26, 1578–1587 (2002).
Lee, J. et al. Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma. Cancer 109, 1561–1569 (2007).
Franko, J. et al. Loss of heterozygosity predicts poor survival after resection of pancreatic adenocarcinoma. J. Gastrointest. Surg. 12, 1664–1672; discussion 1672–1673 (2008).
Salek, C. et al. Evaluation of clinical relevance of examining K-ras, p16 and p53 mutations along with allelic losses at 9p and 18q in EUS-guided fine needle aspiration samples of patients with chronic pancreatitis and pancreatic cancer. World J. Gastroenterol. 13, 3714–3720 (2007).
Kim, S. T. et al. Impact of KRAS mutations on clinical outcomes in pancreatic cancer patients treated with first-line gemcitabine-based chemotherapy. Mol. Cancer Ther. 10, 1993–1999 (2011).
Schultz, N. A. et al. Frequencies and prognostic role of KRAS and BRAF mutations in patients with localized pancreatic and ampullary adenocarcinomas. Pancreas 41, 759–766 (2012).
Boeck, S. et al. KRAS mutation status is not predictive for objective response to anti-EGFR treatment with erlotinib in patients with advanced pancreatic cancer. J. Gastroenterol. 48, 544–548 (2013).
Oliveira-Cunha, M., Hadfield, K. D., Siriwardena, A. K. & Newman, W. EGFR and KRAS mutational analysis and their correlation to survival in pancreatic and periampullary cancer. Pancreas 41, 428–434 (2012).
Ogura, T. 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. 48, 640–646 (2013).
Shin, S. H. et al. Genetic alterations of K-ras, p53, c-erbB-2, and DPC4 in pancreatic ductal adenocarcinoma and their correlation with patient survival. Pancreas 42, 216–222 (2013).
Rachakonda, P. S. et al. Somatic mutations in exocrine pancreatic tumors: association with patient survival. PLOS ONE 8, e60870 (2013).
Sinn, B. V. et al. KRAS mutations in codon 12 or 13 are associated with worse prognosis in pancreatic ductal adenocarcinoma. Pancreas 43, 578–583 (2014).
Kwon, M. J. et al. Low frequency of KRAS mutation in pancreatic ductal adenocarcinomas in Korean patients and its prognostic value. Pancreas 44, 484–492 (2015).
Huang, J. et al. Variant profiling of candidate genes in pancreatic ductal adenocarcinoma. Clin. Chem. 61, 1408–1416 (2015).
Bournet, B. et al. KRAS G12D mutation subtype is a prognostic factor for advanced pancreatic adenocarcinoma. Clin. Transl. Gastroenterol. 7, e157 (2016).
Qian, Z. R. et al. Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma. JAMA Oncol. 4, e173420 (2018).
Bachet, J.-B. et al. S100A2 is a predictive biomarker of adjuvant therapy benefit in pancreatic adenocarcinoma. Eur. J. Cancer 49, 2643–2653 (2013).
Gayral, M. et al. MicroRNAs as emerging biomarkers and therapeutic targets for pancreatic cancer. World J. Gastroenterol. 20, 11199–11209 (2014).
Kapoor, A. et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell 158, 185–197 (2014).
Wilson, C. Y. & Tolias, P. Recent advances in cancer drug discovery targeting RAS. Drug Discov. Today 21, 1915–1919 (2016).
Asati, V., Mahapatra, D. K. & Bharti, S. K. K-Ras and its inhibitors towards personalized cancer treatment: pharmacological and structural perspectives. Eur. J. Med. Chem. 125, 299–314 (2017).
Matera, R. & Saif, M. W. New therapeutic directions for advanced pancreatic cancer: cell cycle inhibitors, stromal modifiers and conjugated therapies. Expert Opin. Emerg. Drugs 22, 223–233 (2017).
Fleming, J. B., Shen, G.-L., Holloway, S. E., Davis, M. & Brekken, R. A. Molecular consequences of silencing mutant K-ras in pancreatic cancer cells: justification for K-ras-directed therapy. Mol. Cancer Res. 3, 413–423 (2005).
Yuan, T. L. et al. Development of siRNA payloads to target KRAS-mutant cancer. Cancer Discov. 4, 1182–1197 (2014).
Xue, W. et al. Small RNA combination therapy for lung cancer. Proc. Natl Acad. Sci. USA 111, E3553–E3561 (2014).
Zorde Khvalevsky, E. et al. Mutant KRAS is a druggable target for pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20723–20728 (2013).
Golan, T. et al. RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients. Oncotarget 6, 24560–24570 (2015).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01676259 (2019).
Kamerkar, S. et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 546, 498–503 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03608631 (2019).
Pecot, C. V. et al. Therapeutic silencing of KRAS using systemically delivered siRNAs. Mol. Cancer Ther. 13, 2876–2885 (2014).
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013).
Lim, S. M. et al. Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor. Angew. Chem. Int. Ed Engl. 53, 199–204 (2014).
Tichauer, R. H. et al. Water distribution within wild-type NRas protein and Q61 mutants during unrestrained QM/MM dynamics. Biophys. J. 115, 1417–1430 (2018).
Mosolits, S., Ullenhag, G. & Mellstedt, H. Therapeutic vaccination in patients with gastrointestinal malignancies. A review of immunological and clinical results. Ann. Oncol. 16, 847–862 (2005).
Toubaji, A. et al. Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers. Cancer Immunol. Immunother. 57, 1413–1420 (2008).
Hartley, M. L., Bade, N. A., Prins, P. A., Ampie, L. & Marshall, J. L. Pancreatic cancer, treatment options, and GI-4000. Hum. Vaccines Immunother. 11, 931–937 (2015).
Quandt, J. et al. Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses. Oncoimmunology 7, e1500671 (2018).
Cohn, A. et al. Whole recombinant saccharomyces cerevisiae yeast expressing ras mutations as treatment for patients with solid tumors bearing ras mutations: results from a phase 1 trial. J. Immunother. 41, 141–150 (2018).
Van Cutsem, E. et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J. Clin. Oncol. 22, 1430–1438 (2004).
Berndt, N., Hamilton, A. D. & Sebti, S. M. Targeting protein prenylation for cancer therapy. Nat. Rev. Cancer 11, 775–791 (2011).
Martin, N. E. et al. A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer. Clin. Cancer Res. 10, 5447–5454 (2004).
Chandra, A. et al. The GDI-like solubilizing factor PDEδ sustains the spatial organization and signalling of Ras family proteins. Nat. Cell Biol. 14, 148–158 (2011).
Zimmermann, G. et al. Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling. Nature 497, 638–642 (2013).
Laheru, D. et al. Integrated preclinical and clinical development of S-trans, trans-farnesylthiosalicylic acid (FTS, Salirasib) in pancreatic cancer. Invest. New Drugs 30, 2391–2399 (2012).
Riely, G. J. et al. A phase II trial of Salirasib in patients with lung adenocarcinomas with KRAS mutations. J. Thorac. Oncol. 6, 1435–1437 (2011).
Morgan, R. J. Jr et al. Phase II trial of bryostatin-1 in combination with cisplatin in patients with recurrent or persistent epithelial ovarian cancer: a California cancer consortium study. Invest. New Drugs 30, 723–728 (2012).
Lugowska, I., Koseła-Paterczyk, H., Kozak, K. & Rutkowski, P. Trametinib: a MEK inhibitor for management of metastatic melanoma. OncoTargets Ther 8, 2251–2259 (2015).
Bodoky, 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 30, 1216–1223 (2012).
Infante, J. R. 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 50, 2072–2081 (2014).
Van Cutsem, E. et al. Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer. Int. J. Cancer 143, 2053–2064 (2018).
Fruman, D. A. & Rommel, C. PI3K and cancer: lessons, challenges and opportunities. Nat. Rev. Drug Discov. 13, 140–156 (2014).
Mahapatra, D. K., Asati, V. & Bharti, S. K. MEK inhibitors in oncology: a patent review (2015–present). Expert Opin. Ther. Pat. 27, 887–906 (2017).
Ning, C. et al. Targeting ERK enhances the cytotoxic effect of the novel PI3K and mTOR dual inhibitor VS-5584 in preclinical models of pancreatic cancer. Oncotarget 8, 44295–44311 (2017).
Kinsey, C. G. et al. Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat. Med. 25, 620–627 (2019).
Bryant, K. L. et al. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat. Med. 25, 628–640 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03825289 (2019).
Shodeinde, A., Ginjupalli, K., Lewis, H. D., Riaz, S. & Barton, B. E. STAT3 inhibition induces apoptosis in cancer cells independent of STAT1 or STAT2. J. Mol. Biochem. 2, 18–26 (2013).
The authors thank E. Buscail for his helpful advice on liquid biopsies in cancer.
The authors declare no competing interests.
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Buscail, L., Bournet, B. & Cordelier, P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol 17, 153–168 (2020). https://doi.org/10.1038/s41575-019-0245-4
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