Affiliations of authors: Department of Gynecologic Oncology and Repro ductive Medicine (YK, WH, CI, CVP, HJD, BZ, TL, JH, NBJ, RR, MT, TM, SP, SYW, CL, YW, AKS), Center for RNAi and Non-Coding RNA (CI, AKS), Department of Pathology (JH, JL), and Department of Cancer Biology (AKS), The University of Texas MD Anderson Cancer Center, Houston, TX; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital and Institute of Obstetrics and Gynecology, Shanghai Medical College of Fudan University, Shanghai, China (YK); Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (TL).
J Natl Cancer Inst. 2013 Oct 2;105(19):1485-95. doi: 10.1093/jnci/djt210. Epub 2013 Sep 23.
We previously found focal adhesion kinase (FAK) inhibition sensitizes ovarian cancer to taxanes; however, the mechanisms are not well understood.
We characterized the biologic response of taxane-resistant and taxane-sensitive ovarian cancer models to a novel FAK inhibitor (VS-6063). We used reverse-phase protein arrays (RPPA) to identify novel downstream targets in taxane-resistant cell lines. Furthermore, we correlated clinical and pathological data with nuclear and cytoplasmic expression of FAK and YB-1 in 105 ovarian cancer samples. Statistical tests were two-sided, and P values were calculated with Student t test or Fisher exact test.
We found that VS-6063 inhibited FAK phosphorylation at the Tyr397 site in a time- and dose-dependent manner. The combination of VS-6063 and paclitaxel markedly decreased proliferation and increased apoptosis, which resulted in 92.7% to 97.9% reductions in tumor weight. RPPA data showed that VS-6063 reduced levels of AKT and YB-1 in taxane-resistant cell lines. FAK inhibition enhanced chemosensitivity in taxane-resistant cells by decreasing YB-1 phosphorylation and subsequently CD44 in an AKT-dependent manner. In human ovarian cancer samples, nuclear FAK expression was associated with increased nuclear YB-1 expression (χ²) = 37.7; P < .001). Coexpression of nuclear FAK and YB-1 was associated with statistically significantly worse median overall survival (24.9 vs 67.3 months; hazard ratio = 2.64; 95% confidence interval = 1.38 to 5.05; P = .006).
We have identified a novel pathway whereby FAK inhibition with VS-6063 overcomes YB-1-mediated paclitaxel resistance by an AKT-dependent pathway. These findings have implications for clinical trials aimed at targeting FAK.
我们之前发现粘着斑激酶（FAK）的抑制作用可使卵巢癌对紫杉烷类药物敏感；但是，其机制尚不清楚。
我们对紫杉烷耐药和紫杉烷敏感的卵巢癌模型对新型 FAK 抑制剂（VS-6063）的生物学反应进行了特征描述。我们使用反相蛋白阵列（RPPA）来鉴定紫杉烷耐药细胞系中的新型下游靶标。此外，我们将临床和病理数据与 105 例卵巢癌样本中的 FAK 和 YB-1 的核和细胞质表达相关联。统计检验为双侧检验，通过 Student t 检验或 Fisher 确切检验计算 P 值。
我们发现 VS-6063 以时间和剂量依赖的方式抑制 Tyr397 位点的 FAK 磷酸化。VS-6063 与紫杉醇的联合使用显著降低了增殖并增加了凋亡，从而使肿瘤重量减少了 92.7%至 97.9%。RPPA 数据显示，VS-6063 降低了紫杉烷耐药细胞系中 AKT 和 YB-1 的水平。FAK 抑制通过 AKT 依赖性方式降低 YB-1 磷酸化，随后降低 CD44，从而增强了紫杉烷耐药细胞的化学敏感性。在人卵巢癌样本中，核 FAK 表达与核 YB-1 表达增加有关（χ²）= 37.7；P <.001）。核 FAK 和 YB-1 的共表达与中位总生存期明显更差相关（24.9 与 67.3 个月；危险比 = 2.64；95%置信区间 = 1.38 至 5.05；P =.006）。
我们已经确定了一种新的途径，通过该途径，FAK 抑制作用与 VS-6063 通过 AKT 依赖性途径克服了 YB-1 介导的紫杉醇耐药性。这些发现对旨在靶向 FAK 的临床试验具有重要意义。
