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Oncogene. 2019 May;38(18):3355-3370. doi: 10.1038/s41388-018-0650-0. Epub 2019 Jan 29.

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

Author information

1
Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA. Erik.Knudsen@roswellpark.org.
2
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA. Erik.Knudsen@roswellpark.org.
3
Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
4
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
5
Department of Pharmacology, Universtiy of Arizona, Tucson, AZ, USA.
6
Cellular and Molecular Medicine, Universtiy of Arizona, Tucson, AZ, USA.
7
Department of Surgery, University of Arizona, Tucson, AZ, USA.
8
Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA. Agnieszka.Witkiewicz@roswellpark.org.
9
Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA. Agnieszka.Witkiewicz@roswellpark.org.

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.

PMID:
30696953
PMCID:
PMC6499706
DOI:
10.1038/s41388-018-0650-0
[Indexed for MEDLINE]
Free PMC Article

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