FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
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DOI：
10.7554/elife.47327
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发表时间：
2019-09-03
期刊：
影响因子：
7.7
通讯作者：
Schlaepfer, David D.
中科院分区：
文献类型：
--
作者：
Diaz Osterman, Carlos J.;Ozmadenci, Duygu;Schlaepfer, David D.
基因拷贝数的改变、肿瘤细胞的干细胞性和铂类化疗耐药的发生与高级别浆液性卵巢癌（HGSOC）的复发有关。干细胞表型涉及Wnt-β-连环蛋白，醛脱氢酶活性，内在铂抗性，和肿瘤球形成与自发增益Kras，Myc和FAK（KMF）基因在一个新的侵袭性小鼠模型卵巢癌。粘附非依赖性FAK信号传导维持KMF和人肿瘤球增殖以及对顺铂细胞毒性的抗性。铂耐药肿瘤球可获得对FAK的生长依赖。因此，在新辅助化疗存活的HGSOC患者肿瘤中观察到FAK酪氨酸磷酸化增加。FAK抑制剂与铂的组合克服了化学抗性并引发细胞凋亡。在敲除和重建细胞中进行的FAK转录组学分析鉴定了135个在HGSOC中升高的靶标，其受FAK活性和β-连环蛋白（包括Myc、多能性和DNA修复基因）调节。这些研究揭示了致癌FAK信号传导作用支持化疗耐药性。
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-beta-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous gains in Kras, Myc and FAK (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 beta-catenin including Myc, pluripotency and DNA repair genes. These studies reveal an oncogenic FAK signaling role supporting chemoresistance.