Paclitaxel-induced mitotic arrest results in a convergence of apoptotic dependencies that can be safely exploited by BCL-X L degradation to overcome cancer chemoresistance

作者：Xingping Qin, Adam Presser, Lissah Johnson, Yusuke Matoba, Brendan Shay, Weiyi Xu, Jonathan Choiniere, Fraser Cameron, Filip Garbicz, Johan Spetz, Stacey Yu, Mary H.C. Florido, Francesca Picucci, Yang Yang, Ronny Drapkin, Ruben D. Carrasco, Sarah J. Hill, Joyce F. Liu, Ursula A. Matulonis, Joan S. Brugge, Bo R. Rueda, Daohong Zhou, Elizabeth H. Stover, Kristopher A. Sarosiek · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.06.24.661170 · 被引用次数：11 · 研究领域：Cell death mechanisms and regulation、Nanoparticle-Based Drug Delivery、Cancer-related Molecular Pathways

Abstract Paclitaxel and other microtubule-targeting agents are cornerstone therapies for diverse cancers, including lung, breast, cervical, pancreatic, and ovarian malignancies. Paclitaxel induces tumor cell apoptosis during mitosis by disrupting microtubule dynamics required for chromosome segregation. However, despite initial responsiveness, many tumors develop resistance, limiting therapeutic durability. Here, we used high-grade serous ovarian carcinoma (HGSOC), the most common and lethal subtype of ovarian cancer, as a model to dissect the mechanisms underlying this resistance. We find that paclitaxel-induced mitotic arrest triggers degradation of the pro-survival protein MCL-1 and upregulation of BCL-XL, followed by inactivating phosphorylation of BCL-XL at Ser62 to promote apoptosis. In resistant cells, this MCL-1 downregulation is insufficient to commit cells to apoptosis but instead results in a transient convergence of apoptotic dependencies by forcing BCL-X L to sequester the pro-apoptotic proteins BIM, BAX, and BAK. During this state, BCL-XL inhibition induces synergistic apoptosis, even in chemoresistant cells. Surprisingly, we also discover that loss of substrate attachment recapitulates this apoptotic convergence both in vitro and in vivo, with HGSOC cells growing in metastasis-promoting malignant ascites displaying heightened apoptotic priming and dependence on BCL-XL relative to solid tumors. In HGSOC xenografts, targeted degradation of BCL-XL using the platel...