The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor–resistant ER ⁺ breast cancer with mitotic aberrations

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.

Simulating cell-free chromatin using preclinical models for cancer-specific biomarker discovery

“…Likewise, for CAMA-1, copy number aberrations detected within cf-chromatin were largely concordant with those from nuclear WGS (Supplementary Fig. S2B) 78 . Furthermore, these copy number profiles were consistent across MNase digestion times (Supplementary Fig.…”

Seize the engine: Emerging cell cycle targets in breast cancer

“…In preclinical models of BC, the blockade of AURKA with its ATP‐competitive inhibitor alisertib induced mitotic spindle defects, mitotic delays and apoptosis, and displayed synergistic effects with the addition of paclitaxel 152–154 . Furthermore, our group recently showed the enhanced sensitivity to AURKAi alisertib, barasertib and tozasertib, of a panel of palbociclib‐resistant BC cells, characterised by an increased incidence of micronuclei and segregation errors 155 …”

“…Another orally active TTKi, CFI‐402257, has shown preclinical monotherapy and taxane‐combination activity in HR + /HER2 − and TNBC models 184,192,193 . Of note, enhanced cytotoxicity has been observed in a subset of CDK4/6i‐resistant models, including those harbouring loss of RB1 155,184,193 . Currently, two phase 1/2 trials are underway evaluating CFI‐402257 in advanced solid tumours and BC.…”

Tumor suppressor heterozygosity and homologous recombination deficiency mediate resistance to front-line therapy in breast cancer

“…Although acquisition of RB1 loss on CDK4/6i is relatively rare in an unselected population, our results demonstrate that RB1 loss under the therapeutic pressure of CDK4/6i is observed almost exclusively in cancers who had only one functional allele of RB1 pretreatment. This has major clinical implications for advanced surveillance strategies and patient selection for clinical trials of precision therapeutic strategies directed against complete RB1 loss 50,51 . Most broadly, these results demonstrate how pre-treatment allelic structure of tumor suppressor genes may predict not only the therapeutic outcome of a particular targeted therapy, but may also forecast the specific mechanism by which a desired therapy will ultimately fail.…”