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FAK 活性维持卵巢癌细胞对铂类化疗的内在和获得性耐药性。

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.

机构信息

Department of Obstetrics, Gynecology and Reproductive Sciences, Moores UCSD Cancer Center, La Jolla, United States.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cellular Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.

出版信息

Elife. 2019 Sep 3;8:e47327. doi: 10.7554/eLife.47327.

DOI:10.7554/eLife.47327
PMID:31478830
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6721800/
Abstract

Gene copy number alterations, tumor cell stemness, and the development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stem phenotypes involving Wnt-β-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in , and (KMF) genes in a new aggressive murine model of ovarian cancer. Adhesion-independent FAK signaling sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neo-adjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance and triggered cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 targets, elevated in HGSOC, that were regulated by FAK activity and β-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance.

摘要

基因拷贝数改变、肿瘤细胞干性和铂类化疗耐药的发展导致高级别浆液性卵巢癌（HGSOC）复发。这里涉及 Wnt-β-catenin、醛脱氢酶活性、内在铂类耐药和肿瘤球形成的干细胞表型与卵巢癌新的侵袭性小鼠模型中 、 和 （KMF）基因的自发获得相关。黏附非依赖性 FAK 信号维持 KMF 和人肿瘤球的增殖以及对顺铂细胞毒性的耐药性。铂类耐药性肿瘤球可以获得对 FAK 生长的依赖性。因此，在接受新辅助化疗的 HGSOC 患者肿瘤中观察到 FAK 酪氨酸磷酸化增加。FAK 抑制剂与铂类联合克服化疗耐药并引发细胞凋亡。跨敲除和重建细胞的 FAK 转录组分析确定了 135 个靶标，这些靶标在 HGSOC 中上调，受 FAK 活性和 β-catenin 调节，包括 Myc、多能性和 DNA 修复基因。这些研究揭示了支持化疗耐药的致癌 FAK 信号转导作用。

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