CDKN1B(p27kip1) enhances drug tolerant persister CTCs by restricting polyploidy following mitotic inhibitors

Abstract

ABSTRACTThe mitotic inhibitor docetaxel (DTX) is often used to treat endocrine-refractory metastatic breast cancer, but initial responses are mitigated as patients eventually have disease progression. Using a cohort ofex vivocultures of circulating tumor cells (CTCs) from patients with heavily pretreated breast cancer (n=18), we find two distinct patterns of DTX susceptibility, independent of clinical treatment history. In CTCs cultured from some patients, treatment with a single dose of DTX results in complete cell killing, associated with accumulation of non-viable polyploid (≥8N) cells arising from endomitosis. In others, a transient viable drug-tolerant persister (DTP) population emerges, ultimately enabling renewed proliferation of CTCs with preserved parental cell ploidy and DTX sensitivity. In these CTC cultures, efficient cell cycle exit generates a ≤4N drug-tolerant state dependent onCDKN1B(p27Kip1). Exposure to DTX triggers stabilization of CDKN1B through AKT-mediated phosphorylation at serine 10. Suppression ofCDKN1Breduces the number of persister CTCs, increases ≥8N mitotic cells and abrogates regrowth after DTX exposure. Thus, CDKN1B-mediated suppression of endomitosis contributes to a reversible persister state following mitotic inhibitors in patient-derived treatment refractory breast cancer cells.Summary in bulletsTransient DTX tolerant persister cells emerge in some patient-derived cultured CTCs.DTX-tolerant persisters restrict endoreduplication and polyploidy through CDKN1 (p27kip1).DTX exposure induces CDKN1B stabilization through AKT mediated phosphorylation at serine 10.Suppression of polyploidy underlies a drug tolerant persister state specific to mitotic inhibitors.