Cell cycle plasticity driven by MTOR signaling: Integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer
| Autor: | Amanda Ruiz, Tun Jie, Agnieszka K. Witkiewicz, Erik S. Knudsen, Shailender S. Chauhan, Vishnu Kumarasamy, Taylor S. Riall, Paris Vail, Sejin Chung, Adam D. Grant, Jared Sivinski |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research endocrine system diseases Cell Plasticity Biology Article 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation CDKN2A E2F Pancreatic cancer Cell Line Tumor Cyclin E Genetics medicine KRAS Biomarkers Tumor Animals Humans Cyclin D1 Molecular Biology Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Kinase TOR Serine-Threonine Kinases Cell Cycle Retinoblastoma Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase 6 Cell cycle medicine.disease Prognosis Xenograft Model Antitumor Assays digestive system diseases Up-Regulation Pancreatic Neoplasms 030104 developmental biology 030220 oncology & carcinogenesis Cancer research CDK4/6 Inhibition Signal transduction Carcinoma Pancreatic Ductal Signal Transduction |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | 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 which 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. |
| Databáze: | OpenAIRE |
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