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

• DOI: 10.1101/2024.02.20.581202
• Publication Date: 2024-02-27T17:56:13Z
• Authors: Elad Horwitz; Taronish D. Dubash; Annamaria Szabolcs; Ben S. Wittner; Johannes Kreuzer; Robert Morris; Aditya Bardia; Brian Chirn; Devon Wiley; Dante Che; Hunter C. Russel; Xcanda Ixchel Her...; Douglas B. Fox; Ezgi Antmen; David T. Ting; Wilhelm Haas; Moshe Sade-Feldman; Shyamala Maheswaran; Daniel A. Haber
• Keywords: Multidrug tolerance

ABSTRACT The 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 of ex vivo cultures circulating tumor cells (CTCs) from with heavily pretreated cancer (n=18), we find two distinct patterns DTX susceptibility, independent clinical treatment history. In CTCs cultured some patients, single dose results in complete cell killing, associated accumulation non-viable polyploid (≥8N) arising endomitosis. others, transient viable drug-tolerant persister (DTP) population emerges, ultimately enabling renewed proliferation preserved parental ploidy and sensitivity. these CTC cultures, efficient cycle exit generates ≤4N state dependent on CDKN1B (p27 Kip1 ). Exposure triggers stabilization through AKT-mediated phosphorylation at serine 10. Suppression reduces the number CTCs, increases ≥8N abrogates regrowth after exposure. Thus, CDKN1B-mediated suppression endomitosis contributes reversible following inhibitors patient-derived refractory cells. Summary bullets Transient tolerant emerge CTCs. DTX-tolerant persisters restrict endoreduplication polyploidy CDKN1 kip 1 exposure induces AKT mediated underlies drug specific inhibitors.