Journal Article

YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation

Tsuji, Takahiro, Aburaya, Shunsuke, Nomizo, Takashi, Kim, Young Hak, Yoshimura, Yasushi, Furugaki, Koh, Ueda, Mitsuyoshi, Yoshida, Hironori, Yasuda, Yuto, Hirai, Toyohiro, Yamamoto Funazo, Tomoko, Ajimizu, Hitomi, Yamazoe, Masatoshi, Ozasa, Hiroaki, Aoki, Wataru, Sakamori, Yuichi, Wake, Hiroaki

2020

Overview

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. Relapse is a limitation for the efficacy of the anaplastic lymphoma kinase (ALK)-inhibitor alectinib in ALK-rearranged lung cancer. Here, the authors show that YAP1 activation upon alectinib treatment leads to therapy resistance and that inhibiting both YAP1 and ALK leads to longer tumor remission in mice.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/1 / 14/63 / 38/77 / 38/89 / 631/67/1612/1350 / 692/308/2778 / 692/308/575 / 692/4028/67/1059/2326 / 692/4028/67/1059/602 / 82/47 / 82/80 / 96/1 / 96/2 / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Anaplastic Lymphoma Kinase - genetics / Anaplastic Lymphoma Kinase - metabolism / Animals / Apoptosis / Apoptosis - drug effects / Bcl-x protein / Carbazoles - administration & dosage / Cell culture / Cell Line, Tumor / Cell Survival - drug effects / Combinatorial analysis / Enzyme inhibitors / Female / Gene Rearrangement - drug effects / Humanities and Social Sciences / Humans / Kinases / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - physiopathology / Lymphoma / Male / Mcl-1 protein / Mice / Mice, Inbred BALB C / multidisciplinary / Neoplasm Recurrence, Local - drug therapy / Neoplasm Recurrence, Local - genetics / Neoplasm Recurrence, Local - metabolism / Neoplasm Recurrence, Local - physiopathology / Patients / Piperidines - administration & dosage / Protein Kinase Inhibitors - administration & dosage / Protein-tyrosine kinase / Proteins / Remission / Science / Science (multidisciplinary) / Survival / Transcription Factors - genetics / Transcription Factors - metabolism / Tumor cells / Tumors / Xenografts / Xenotransplantation / Yes-associated protein