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 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 charac...

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Veröffentlicht in:Science advances 2022-09, Vol.8 (36), p.eabq4293-eabq4293
Hauptverfasser: Soria-Bretones, Isabel, Thu, Kelsie L., Silvester, Jennifer, Cruickshank, Jennifer, El Ghamrasni, Samah, Ba-alawi, Wail, Fletcher, Graham C., Kiarash, Reza, Elliott, Mitchell J., Chalmers, Jordan J., Elia, Andrea C., Cheng, Albert, Rose, April A. N., Bray, Mark R., Haibe-Kains, Benjamin, Mak, Tak W., Cescon, David W.
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Sprache:eng
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Zusammenfassung: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abq4293