Candiolo Cancer Institute, FPO-IRCCS, SP 142 km 3.95, 10060, Candiolo, Italy.
Candiolo Cancer Institute, FPO-IRCCS, SP 142 km 3.95, 10060, Candiolo, Italy; University of Torino, Department of Oncology, SP 142 km 3.95, 10060, Candiolo, Italy.
Neoplasia. 2017 Dec;19(12):1012-1021. doi: 10.1016/j.neo.2017.10.003. Epub 2017 Nov 11.
The Yes-associated protein (YAP) is a transcriptional co-activator upregulating genes that promote cell growth and inhibit apoptosis. The main dysregulation of the Hippo pathway in tumors is due to YAP overexpression, promoting epithelial to mesenchymal transition, cell transformation, and increased metastatic ability. Moreover, it has recently been shown that YAP plays a role in sustaining resistance to targeted therapies as well. In our work, we evaluated the role of YAP in acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in lung cancer. In EGFR-addicted lung cancer cell lines (HCC4006 and HCC827) rendered resistant to several EGFR inhibitors, we observed that resistance was associated to YAP activation. Indeed, YAP silencing impaired the maintenance of resistance, while YAP overexpression decreased the responsiveness to EGFR inhibitors in sensitive parental cells. In our models, we identified the AXL tyrosine kinase receptor as the main YAP downstream effector responsible for sustaining YAP-driven resistance: in fact, AXL expression was YAP dependent, and pharmacological or genetic AXL inhibition restored the sensitivity of resistant cells to the anti-EGFR drugs. Notably, YAP overactivation and AXL overexpression were identified in a lung cancer patient upon acquisition of resistance to EGFR TKIs, highlighting the clinical relevance of our in vitro results. The reported data demonstrate that YAP and its downstream target AXL play a crucial role in resistance to EGFR TKIs and suggest that a combined inhibition of EGFR and the YAP/AXL axis could be a good therapeutic option in selected NSCLC patients.
Yes 相关蛋白 (YAP) 是一种转录共激活因子，可上调促进细胞生长和抑制细胞凋亡的基因。Hippo 通路在肿瘤中的主要失调是由于 YAP 过表达，促进上皮间质转化、细胞转化和增加转移能力。此外，最近表明 YAP 在维持对靶向治疗的耐药性方面也发挥作用。在我们的工作中，我们评估了 YAP 在肺癌中对表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂获得性耐药中的作用。在对几种 EGFR 抑制剂产生耐药的 EGFR 依赖型肺癌细胞系 (HCC4006 和 HCC827) 中，我们观察到耐药性与 YAP 激活有关。事实上，YAP 沉默削弱了耐药性的维持，而 YAP 过表达降低了敏感亲本细胞对 EGFR 抑制剂的反应性。在我们的模型中，我们确定了 AXL 酪氨酸激酶受体作为维持 YAP 驱动的耐药性的主要 YAP 下游效应物：事实上，AXL 表达依赖于 YAP，AXL 的药理学或遗传抑制恢复了耐药细胞对抗 EGFR 药物的敏感性。值得注意的是，在一名对 EGFR TKI 获得性耐药的肺癌患者中发现了 YAP 过激活和 AXL 过表达，突出了我们体外结果的临床相关性。所报道的数据表明，YAP 和其下游靶标 AXL 在 EGFR TKI 耐药中发挥着至关重要的作用，并表明联合抑制 EGFR 和 YAP/AXL 轴可能是 NSCLC 患者的一种良好治疗选择。
