The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor-resistant ER⁺ breast cancer with mitotic aberrations.

ABSTRACT: Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER⁺ breast cancer. However, acquired resistance to CDK4/6i invariably develops, and the molecular phenotypes and exploitable vulnerabilities associated with resistance are not yet fully characterized. We developed a panel of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids and demonstrate that a subset of resistant models accumulates mitotic segregation errors and micronuclei, displaying increased sensitivity to inhibitors of mitotic checkpoint regulators TTK and Aurora kinase A/B. RB1 loss, a well-recognized mechanism of CDK4/6i resistance, causes such mitotic defects and confers enhanced sensitivity to TTK inhibition. In these models, inhibi

SUBMITTER: Soria-Bretones I 

PROVIDER: S-EPMC9451148 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature