Pancreatic ductal adenocarcinoma (PDAC), like many KRAS-driven tumors, preferentially loses CDKN2A that encodes an endogenous CDK4/6 inhibitor to bypass the RB-mediated cell cycle suppression. Analysis of a panel of patient-derived cell lines and matched xenografts indicated that many pancreatic cancers have intrinsic resistance to CDK4/6 inhibition that is not due to any established mechanism or published biomarker. Rather, there is a KRAS-dependent rapid adaptive response that leads to the upregulation of cyclin proteins, which participate in functional complexes to mediate resistance. In vivo, the degree of response is associated with the suppression of a gene expression signature that is strongly prognostic in pancreatic cancer. Resistance is associated with an adaptive gene expression signature that is common to multiple kinase inhibitors, but is attenuated with MTOR inhibitors. Combination treatment with MTOR and CDK4/6 inhibitors had potent activity across a large number of patient-derived models of PDAC underscoring the potential clinical efficacy.
Subscribe to Journal
Get full journal access for 1 year
only $7.98 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
RNA sequencing data are deposited in GEO: GSE113922.
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.
Cheema AR, O’Reilly EM. Management of metastatic pancreatic adenocarcinoma. Surg Clin North Am. 2016;96:1391–414.
Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV, et al. Pancreatic cancer. Nat Rev Dis Prim. 2016;2:16022.
Knudsen ES, O’Reilly EM, Brody JR, Witkiewicz AK. Genetic diversity of pancreatic ductal adenocarcinoma and opportunities for precision medicine. Gastroenterology. 2015;150:48–63.
Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378:607–20.
Ottaiano A, Capozzi M, De Divitiis C, De Stefano A, Botti G, Avallone A, et al. Gemcitabine mono-therapy versus gemcitabine plus targeted therapy in advanced pancreatic cancer: a meta-analysis of randomized phase III trials. Acta Oncol. 2017;56:377–83.
Cowan RW, Maitra A. Genetic progression of pancreatic cancer. Cancer J. 2014;20:80–4.
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.
Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015;14:130–46.
Witkiewicz AK, Knudsen KE, Dicker AP, Knudsen ES. The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments. Cell Cycle. 2011;10:2497–503.
Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444:633–7.
Serrano M, Gomez-Lahoz E, DePinho RA, Beach D, Bar-Sagi D. Inhibition of ras-induced proliferation and cellular transformation by p16INK4. Science. 1995;267:249–52.
Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov. 2016;6:740–53.
Kwong LN, Costello JC, Liu H, Jiang S, Helms TL, Langsdorf AE, et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med. 2012;18:1503–10.
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. 2017;67:2142–55.
Gao H, Korn JM, Ferretti S, Monahan JE, Wang Y, Singh M, et al. High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response. Nat Med. 2015;21:1318–25.
Witkiewicz AK, Borja NA, Franco J, Brody JR, Yeo CJ, Mansour J, et al. Selective impact of CDK4/6 suppression on patient-derived models of pancreatic cancer. Oncotarget. 2015;6:15788–801.
Franco J, Witkiewicz AK, Knudsen ES. CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget. 2014;5:6512–25.
Franco J, Balaji U, Freinkman E, Witkiewicz AK, Knudsen ES. Metabolic reprogramming of pancreatic cancer mediated by CDK4/6 inhibition elicits unique vulnerabilities. Cell Rep. 2016;14:979–90.
Heilmann AM, Perera RM, Ecker V, Nicolay BN, Bardeesy N, Benes CH, et al. CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers. Cancer Res. 2014;74:3947–58.
Knudsen ES, Balaji U, Mannakee B, Vail P, Eslinger C, Moxom C. et al. Pancreatic cancer cell lines as patient-derived avatars: genetic characterisation and functional utility. Gut. 2017;63:508–20.
Witkiewicz AK, Balaji U, Eslinger C, McMillan E, Conway W, Posner B, et al. Integrated patient-derived models delineate individualized therapeutic vulnerabilities of pancreatic cancer. Cell Rep. 2016;16:2017–31.
Cancer Genome Atlas Research N, Network CGAR. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell. 2017;32:185–203 e113.
Collisson EA, Sadanandam A, Olson P, Gibb WJ, Truitt M, Gu S, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med. 2011;17:500–3.
Herrera-Abreu MT, Palafox M, Asghar U, Rivas MA, Cutts RJ, Garcia-Murillas I. et al. Early Adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res. 2016;76:2301–13.
Teh JLF, Cheng PF, Purwin TJ, Nikbakht N, Patel P, Chervoneva I. et al. In vivo E2F reporting reveals efficacious schedules of MEK1/2-CDK4/6 targeting and mTOR-S6 resistance mechanisms. Cancer Discov. 2018;8:568–81.
Duronio RJ, Xiong Y. Signaling pathways that control cell proliferation. Cold Spring Harb Perspect Biol. 2013;5:a008904.
Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, et al. Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell. 2016;29:255–69.
Yoshida A, Lee EK, Diehl JA. Induction of therapeutic senescence in vemurafenib-resistant melanoma by extended inhibition of CDK4/6. Cancer Res. 2016;76:2990–3002.
Zhang J, Xu K, Liu P, Geng Y, Wang B, Gan W, et al. Inhibition of Rb phosphorylation leads to mTORC2-mediated activation of Akt. Mol Cell. 2016;62:929–42.
Russo AA, Tong L, Lee JO, Jeffrey PD, Pavletich NP. Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. Nature. 1998;395:237–43.
Raspe E, Coulonval K, Pita JM, Paternot S, Rothe F, Twyffels L, et al. CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib. EMBO Mol Med. 2017;9:1052–66.
Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 2009;10:307–18.
Duncan JS, Whittle MC, Nakamura K, Abell AN, Midland AA, Zawistowski JS, et al. Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell. 2012;149:307–21.
Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel E, et al. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov. 2011;1:248–59.
Gao S, Luo Y, Wu X, Li Y, Zhou Y, Lyu R, et al. EB1 phosphorylation mediates the functions of ASK1 in pancreatic cancer development. Oncotarget. 2017;8:98233–41.
Ono H, Basson MD, Ito H. PTK6 promotes cancer migration and invasion in pancreatic cancer cells dependent on ERK signaling. PLoS ONE. 2014;9:e96060.
Knudsen ES, Witkiewicz AK. The strange case of CDK4/6 inhibitors: mechanisms, resistance, and combination strategies. Trends Cancer. 2017;3:39–55.
Sherr CJ, Beach D, Shapiro GI. Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov. 2016;6:353–67.
Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3:1427–38.
Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, Del Prado M, Lallena MJ. et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014;32:825–37.
Gong X, Litchfield LM, Webster Y, Chio LC, Wong SS, Stewart TR, et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK6 inhibitor abemaciclib. Cancer Cell. 2017;32:761–76 e766.
Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13:1501–12.
Patel P, Tsiperson V, Gottesman SRS, Somma J, Blain SW. Dual inhibition of CDK4 and CDK2 via targeting p27 tyrosine phosphorylation induces a potent and durable response in breast cancer cells. Mol Cancer Res. 2018;16:361–77.
Malumbres M, Sotillo R, Santamaria D, Galan J, Cerezo A, Ortega S, et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell. 2004;118:493–504.
Driscoll DR, Karim SA, Sano M, Gay DM, Jacob W, Yu J, et al. mTORC2 signaling drives the development and progression of pancreatic cancer. Cancer Res. 2016;76:6911–23.
Kozar K, Ciemerych MA, Rebel VI, Shigematsu H, Zagozdzon A, Sicinska E, et al. Mouse development and cell proliferation in the absence of D-cyclins. Cell. 2004;118:477–91.
Yuan TL, Amzallag A, Bagni R, Yi M, Afghani S, Burgan W, et al. Differential effector engagement by oncogenic KRAS. Cell Rep. 2018;22:1889–902.
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.
Knudsen ES, Wang JY. Differential regulation of retinoblastoma protein function by specific Cdk phosphorylation sites. J Biol Chem. 1996;271:8313–20.
Johnson GL, Stuhlmiller TJ, Angus SP, Zawistowski JS, Graves LM. Molecular pathways: adaptive kinome reprogramming in response to targeted inhibition of the BRAF-MEK-ERK pathway in cancer. Clin Cancer Res. 2014;20:2516–22.
The authors thank all members of the laboratory group and colleagues in the discussion and preparation of this paper. The research was supported by a grant to AKW from the NCI.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Knudsen, E.S., Kumarasamy, V., Ruiz, A. et al. Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer. Oncogene 38, 3355–3370 (2019). https://doi.org/10.1038/s41388-018-0650-0
Cancer Research (2021)
Acta Pharmacologica Sinica (2021)
AMPK Is the Crucial Target for the CDK4/6 Inhibitors Mediated Therapeutic Responses in PANC-1 and MIA PaCa-2 Pancreatic Cancer Cell Lines
A cyclin D-CDK6 dimer helps to reshuffle cyclin-dependent kinase inhibitors (CKI) to overcome TGF-beta-mediated arrest and maintain CDK2 activity
Cell Cycle (2021)
Design, synthesis, and biological evaluation of 2,6,7-substituted pyrrolo[2,3-d]pyrimidines as cyclin dependent kinase inhibitor in pancreatic cancer cells
Bioorganic & Medicinal Chemistry Letters (2021)