biostudies-literatureUnknown8(36)Soria-Bretones IInhibitors 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. <i>RB1</i> loss, a well-recognized mechanism of CDK4/6i resistance, causes such mitotic defects and confers enhanced sensitivity to TTK inhibition. In these models, inhibiScience advanceseabq4293https://www.ebi.ac.uk/biostudies/studies/S-EPMC9451148biostudies-literatureThe spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor-resistant ER⁺ breast cancer with mitotic aberrations.PMC9451148Kiarash RMak TWFletcher GCEl Ghamrasni SThu KLCheng ACruickshank JCescon DWElliott MJRose AANSilvester JChalmers JJElia ACBray MRBa-Alawi WSoria-Bretones IHaibe-Kains BfalseThe spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor-resistant ER⁺ breast cancer with mitotic aberrations.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. <i>RB1</i> loss, a well-recognized mechanism of CDK4/6i resistance, causes such mitotic defects and confers enhanced sensitivity to TTK inhibition. In these models, inhibi2022-01-01T00:00:00Z2022 Sep2026-05-28T21:28:12.841Z2025-02-19T03:24:31.202ZS-EPMC94511483607039110.1126/sciadv.abq4293