Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship.
Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship.
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DOI：
10.1126/scitranslmed.3008639
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发表时间：
2014-05-21
影响因子：
17.1
通讯作者：
Pachter JA
中科院分区：
文献类型：
--
作者：
Shapiro IM;Kolev VN;Vidal CM;Kadariya Y;Ring JE;Wright Q;Weaver DT;Menges C;Padval M;McClatchey AI;Xu Q;Testa JR;Pachter JA
靶向治疗的目标是将一种选择性药物与可预测药物敏感性的基因损伤相匹配。在一组多样的癌细胞系中，我们发现对粘着斑激酶（FAK）抑制最为敏感的细胞，其NF2肿瘤抑制基因产物——神经纤维瘤蛋白2（Merlin）的表达存在缺陷。在恶性胸膜间皮瘤（MPM）中，Merlin的表达常常缺失，这是一种由石棉诱发的侵袭性癌症，治疗选择有限。我们的数据表明，在体外实验和肿瘤异种移植模型中，Merlin低表达预示着MPM细胞对FAK抑制剂VS - 4718的敏感性增强。用阻断抗体破坏MPM细胞间或细胞与细胞外基质（ECM）的接触表明，Merlin阴性的MPM细胞中较弱的细胞间黏附导致它们对细胞 - ECM诱导的FAK信号传导有更大的依赖性。这就解释了为什么Merlin阴性细胞易受FAK抑制剂治疗的影响。此外，我们验证了醛脱氢酶（ALDH）是MPM中癌症干细胞（CSCs）的标志物，癌症干细胞被认为是介导化疗后肿瘤复发的细胞群体。培美曲塞和顺铂作为MPM的标准治疗药物会使癌症干细胞富集，而FAK抑制剂治疗则优先清除这些细胞。这些临床前研究结果为在MPM患者中开展一项临床试验提供了理论依据，即一线化疗后使用FAK抑制剂单药治疗。基于这种设计，FAK抑制剂由于能减少癌症干细胞并具有强大的抗肿瘤作用，有可能诱导出更持久的临床反应。此外，我们的数据表明，Merlin阴性肿瘤患者可能尤其能从FAK抑制剂治疗中获益。
The goal of targeted therapy is to match a selective drug with a genetic lesion that predicts for drug sensitivity. In a diverse panel of cancer cell lines, we found that the cells most sensitive to focal adhesion kinase (FAK) inhibition are deficient in the expression of the NF2 tumor suppressor gene product, Merlin. Merlin expression is often lost in malignant pleural mesothelioma (MPM), an asbestos-induced aggressive cancer with limited treatment options. Our data demonstrate that low Merlin expression predicts for increased sensitivity of MPM cells to a FAK inhibitor, VS-4718, in vitro and in tumor xenograft models. Disruption of MPM cell-cell or cell-extracellular matrix (ECM) contacts with blocking antibodies suggests that weak cell-cell adhesions in Merlin-negative MPM cells lead to their greater dependence on cell-ECM-induced FAK signaling. This provides one explanation of why Merlin-negative cells are vulnerable to FAK inhibitor treatment. Furthermore, we validated ALDH as a marker of cancer stem cells (CSCs) in MPM, a cell population thought to mediate tumor relapse after chemotherapy. Whereas pemetrexed and cisplatin, standard-of-care agents for MPM, enrich for CSCs, FAK inhibitor treatment preferentially eliminates these cells. These preclinical results provide the rationale for a clinical trial in MPM patients using a FAK inhibitor as a single agent after first-line chemotherapy. With this design, the FAK inhibitor could potentially induce a more durable clinical response due to reduction of CSCs along with a strong antitumor effect. Furthermore, our data suggest that patients with Merlin-negative tumors may especially benefit from FAK inhibitor treatment.
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影响因子：
28.2
作者：
Shibue T;Brooks MW;Inan MF;Reinhardt F;Weinberg RA
通讯作者：
Weinberg RA
影响因子：
4.6
作者：
Guan, Jun-Lin
通讯作者：
Guan, Jun-Lin
影响因子：
11.2
作者：
Roberts, Walter Gregory;Ung, Ethan;Vajdos, Felix
通讯作者：
Vajdos, Felix
影响因子：
5.7
作者：
Breuleux M;Klopfenstein M;Stephan C;Doughty CA;Barys L;Maira SM;Kwiatkowski D;Lane HA
通讯作者：
Lane HA
影响因子：
6.2
作者：
Flaiz, C.;Utermark, T.;Hanemann, C. O.
通讯作者：
Hanemann, C. O.