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

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.

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Data deposition

RNA sequencing data are deposited in GEO: GSE113922.

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Acknowledgements

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.

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Study concept and design: ESK and AKW. Acquisition of data: VK, AR, JS, SC, and ESK. Analysis and interpretation of data: ESK, VK, AR, JS, SC, AG, and PV. Bioinformatics: PV and AG. Material support: TJ, TSR, and AKW. Study supervision: AKW and ESK. Funding: AKW and ESK.

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Correspondence to Erik S. Knudsen or Agnieszka K. Witkiewicz.

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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

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