Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer

Erik S. Knudsen, Vishnu Kumarasamy, Amanda Ruiz, Jared Sivinski, Sejin Chung, Adam Grant, Paris Vail, Shailender S. Chauhan, Tun Jie, Taylor S. Riall, Agnieszka K. Witkiewicz

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
JournalOncogene
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Knudsen, E. S., Kumarasamy, V., Ruiz, A., Sivinski, J., Chung, S., Grant, A., Vail, P., Chauhan, S. S., Jie, T., Riall, T. S., & Witkiewicz, A. K. (2019). Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer. Oncogene. https://doi.org/10.1038/s41388-018-0650-0