The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor–resistant ER+ breast cancer with mitotic aberrations
Menée à l'aide de lignées cellulaires de cancer du sein, d'organoïdes dérivés de tumeurs de patientes et de xénogreffes sur des modèles murins, cette étude met en évidence l'intérêt de cibler le point de contrôle de l'assemblage du fuseau mitotique pour supprimer les tumeurs mammaires ER+ dont les cellules présentent des aberrations mitotiques et une résistance aux inhibiteurs CDK4/6
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. The TTK inhibitor CFI-402257 is a potential therapy for some cyclin-dependent kinase 4/6 inhibitor-resistant ER+ breast cancers.
Science Advances 2022