CFI-402257

The 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 widely used as first-line treatments for metastatic ER+ breast cancer. However, acquired resistance to CDK4/6i inevitably occurs, and the molecular features and potential vulnerabilities associated with this resistance are not yet fully understood. To address this, we developed a panel of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids. Our findings show that a subset of resistant models accumulate mitotic segregation errors and micronuclei, making them more sensitive to inhibitors of mitotic checkpoint regulators such as TTK and Aurora kinase A/B. Loss of RB1, a well-established mechanism of CDK4/6i resistance, leads to these mitotic defects and increases sensitivity to TTK inhibition. In these models, treatment with the TTK inhibitor CFI-402257 induces premature chromosome segregation, resulting in excessive mitotic errors, DNA damage, and cell death. These results suggest that TTK inhibition with CFI-402257 could be a promising therapeutic strategy for a specific group of ER+ breast cancer patients who have developed resistance to CDK4/6i.