期刊
CANCER DISCOVERY
卷 12, 期 2, 页码 356-371出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-20-1726
关键词
-
类别
资金
- Cancer Couch Foundation
- Shen Family Fund
- Smith Fund for Cancer Research
- Breast Cancer Research Foundation
- NIH Cancer Center Support Grant [P30 CA008748]
- Translational Research Oncology Training Fellowship (MSKCC)
- NIH [P30 CA008748, R01234361, R01 GM121505, R01 GM132386]
- Susan G. Komen Foundation [CCR15330331]
- Instituto de Salud Carlos III [CPII19/00033]
- NIH
- National Science Foundation
- Parker Institute for Cancer Immunotherapy
- Relay Therapeutics
- Entasis Therapeutics
- Silicon Therapeutics
- EMD Serono (Merck KGaA)
- AstraZeneca
- Vir Biotechnology
- Bayer
- XtalPi
- Foresite Laboratories
- Molecular Sciences Software Institute
- Starr Cancer Consortium
- Open Force Field Consortium
- Cycle for Survival
- Louis V. Gerstner Young Investigator Award
- Sloan Kettering Institute
This study identifies CDK4/6 kinase activation as a common mechanism in oncogenic signaling-induced proliferation and develops a new strategy for inhibiting CDK4/6 kinases to overcome resistance.
Cyclin-dependent kinases 4 and 6 (CDK4/6) represent a major therapeutic vulner-ability for breast cancer. The kinases are clinically targeted via ATP competitive inhibitors (CDK4/6i); however, drug resistance commonly emerges over time. To understand CDK4/6i resistance, we surveyed over 1,300 breast cancers and identifi ed several genetic alterations (e.g., FAT1, PTEN, or ARID1A loss) converging on upregulation of CDK6. Mechanistically, we demonstrate CDK6 causes resistance by inducing and binding CDK inhibitor INK4 proteins (e.g., p18(INK4C)). In vitro binding and kinase assays together with physical modeling reveal that the p18 (INK4C)-cyclin D-CDK6 complex occludes CDK4/6i binding while only weakly suppressing ATP binding. Suppression of INK4 expres-sion or its binding to CDK6 restores CDK4/6i sensitivity. To overcome this constraint, we developed bifunctional degraders conjugating palbociclib with E3 ligands. Two resulting lead compounds potently degraded CDK4/6, leading to substantial antitumor effects in vivo , demonstrating the promising thera-peutic potential for retargeting CDK4/6 despite CDK4/6i resistance. SIGNIFICANCE: CDK4/6 kinase activation represents a common mechanism by which oncogenic sign-aling induces proliferation and is potentially targetable by ATP competitive inhibitors. We identify a CDK6-INK4 complex that is resilient to current-generation inhibitors and develop a new strategy for more effective inhibition of CDK4/6 kinases.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据