INK4 Tumor Suppressor Proteins Mediate Resistance to CDK4/6 Kinase Inhibitors.

ABSTRACT: Cyclin-dependent kinases 4 and 6 (CDK4/6) represent a major therapeutic vulnerability 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 identified 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 e

SUBMITTER: Li Q 

PROVIDER: S-EPMC8831444 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature