YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation
YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation
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YAP1通过促凋亡蛋白调控介导阿莱替尼诱导ALK重排的肺癌细胞存活
DOI：
10.1038/s41467-019-13771-5
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发表时间：
2020-01-03
影响因子：
16.6
通讯作者：
Hirai, Toyohiro
中科院分区：
文献类型：
--
作者：
Tsuji, Takahiro;Ozasa, Hiroaki;Hirai, Toyohiro
尽管第二代间变性淋巴瘤激酶（ALK）抑制剂alectinib在ALK重排肺癌患者中具有良好的临床疗效，但仍有部分肿瘤细胞存活并最终复发，这可能成为实现治愈的障碍。目前关于肿瘤细胞对alectinib的初始存活机制的信息有限。使用患者源性细胞系模型，我们在本文中证明，癌细胞通过激活介导抗凋亡因子Mcl-1和Bcl-xL表达的Yes相关蛋白1（YAP 1）在alectinib治疗后存活，与alectinib单药治疗相比，对YAP 1和ALK的联合抑制可使ALK重排异种移植物的肿瘤缓解时间更长。这些结果表明，抑制YAP 1是ALK抑制剂联合治疗的候选药物，可使ALK重排肺癌患者达到完全缓解。
Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer.