CDKN1B (p27/kip1) enhances drug-tolerant persister CTCs by restricting polyploidy following mitotic inhibitors

• 成果类型: Article
• 署名作者: Horwitz, Elad; Dubash, Taronish D.; Szabolcs, Annamaria; Wittner, Ben S.; Kreuzer, Johannes; Morris, Robert; Bardia, Aditya; Chirn, Brian; Wiley, Devon; Che, Dante; Russell, Hunter C.; Lopez, Xcanda Ixchel Herrera; Fox, Douglas B.; Antmen, Ezgi; Burr, Risa; Ting, David T.; Haas, Wilhelm; Sade-Feldman, Moshe; Maheswaran, Shyamala; Haber, Daniel A.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14517
• DOI: 10.1073/pnas.2507203122
• 发表日期: 2025-07-07
• 关键词: cyclin-dependent kinase; breast-tumor cells; cancer-cells; phosphorylates p27(kip1); p27; GROWTH; state; progression; expression; STABILITY

摘要

The mitotic inhibitor docetaxel (DTX) is often used to treat endocrine-refractory metastatic breast cancer, but initial responses are mitigated as patients develop disease progression. Using a cohort of ex vivo cultured circulating tumor cells (CTCs) from patients with heavily pretreated breast cancer (n=18), we find distinct patterns of response to DTX, which are intrinsic and independent of past clinical treatment with taxanes. In some CTC cultures, treatment with a single dose of DTX results in complete cell killing, associated with accumulation of nonviable polyploid (>= 8 N) cells arising from endomitosis. In other CTC cultures, a transient viable drug-tolerant persister (DTP) population emerges, ultimately enabling renewed proliferation of CTCs with preserved parental cell ploidy and restored DTX sensitivity identical to that of the pretreated culture. In these CTCs, efficient cell cycle exit generates a <= 4 N drug-tolerant state dependent on CDKN1B (p27/kip1). Exposure to DTX triggers stabilization of CDKN1B through AKT-mediated phosphorylation at serine 10. Suppression of CDKN1B reduces the number of persister CTCs, increases >= 8 N mitotic cells and abrogates regrowth after DTX exposure. Thus, CDKN1B-mediated suppression of endomitosis contributes to the initiation of a reversible drug-tolerant persister state following mitotic inhibitors in advanced patient-derived breast cancer cells.