Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor
| Autor: | Xinmeng Jasmine Mu, Meirong Xu, Shahram Salek-Ardakani, Cinthia Costa-Jones, Lisa Nguyen, James Solowiej, David Looper, Scott L. Weinrich, Robert Louis Hoffman, Sutton Scott Channing, Sacha Ninkovic, Kephart Susan Elizabeth, Sherry Niessen, John Chionis, Jadwiga Bienkowska, Kevin Daniel Freeman-Cook, Rose Ann Ferre, John Lapek, Cecilia Oderup, Jordan Carelli, Cathy Zhang, Nanni Huser, Elizabeth A. McMillan, Asako Nagata, Martha A. Ornelas, Brion W. Murray, Douglas Carl Behenna, Koleen Eisele, Todd VanArsdale, Zhou Zhu, Zhengyan Kan, Chaoting Liu, Nichol Miller, Zehnder Luke Raymond, Michael A. White, Ying Ding, Nathan V. Lee, Jonathan Almaden, Qin Zhang, Tran Khanh Tuan, Ping Wei, Stephen Dann, Britton Boras, Tim S. Wang, Ravi Visswanathan, You-Ai He, Michele McTigue, Elizabeth Wilson |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Cancer Research Cyclin E Palbociclib Neoplasms medicine Humans Oncogene biology business.industry Cell Cycle Cyclin-Dependent Kinase 2 Cyclin-dependent kinase 2 Cyclin-Dependent Kinase 4 Cancer Cyclin-Dependent Kinase 6 Cell cycle medicine.disease Immune checkpoint Oncology Cancer research biology.protein Female Cyclin-dependent kinase 6 biological phenomena cell phenomena and immunity business |
| Zdroj: | Cancer Cell. 39:1404-1421.e11 |
| ISSN: | 1535-6108 |
| Popis: | Summary The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival in HR+/HER2− breast cancer when combined with anti-hormonals. We sought to discover PAL resistance mechanisms in preclinical models and through analysis of clinical transcriptome specimens, which coalesced on induction of MYC oncogene and Cyclin E/CDK2 activity. We propose that targeting the G1 kinases CDK2, CDK4, and CDK6 with a small-molecule overcomes resistance to CDK4/6 inhibition. We describe the pharmacodynamics and efficacy of PF-06873600 (PF3600), a pyridopyrimidine with potent inhibition of CDK2/4/6 activity and efficacy in multiple in vivo tumor models. Together with the clinical analysis, MYC activity predicts (PF3600) efficacy across multiple cell lineages. Finally, we find that CDK2/4/6 inhibition does not compromise tumor-specific immune checkpoint blockade responses in syngeneic models. We anticipate that (PF3600), currently in phase 1 clinical trials, offers a therapeutic option to cancer patients in whom CDK4/6 inhibition is insufficient to alter disease progression. |
| Databáze: | OpenAIRE |
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