The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor–resistant ER <sup>+</sup> breast cancer with mitotic aberrations
Isabel Soria‐Bretones, Kelsie L. Thu, Jennifer Silvester, Jennifer Cruickshank, Samah El Ghamrasni, Wail Ba-Alawi, Graham C. Fletcher, Reza Kiarash, Mitchell J. Elliott, Jordan J. Chalmers, Andrea C. Elia, Albert Cheng, April A. N. Rose, Mark R. Bray, Benjamin Haibe‐Kains, Tak W. Mak, David W. Cescon
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, inhibition of TTK with CFI-402257 induces premature chromosome segregation, leading to excessive mitotic segregation errors, DNA damage, and cell death. These findings nominate the TTK inhibitor CFI-402257 as a therapeutic strategy for a defined subset of ER + breast cancer patients who develop resistance to CDK4/6i.