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

Takahiro Tsuji, Hiroaki Ozasa (), Wataru Aoki, Shunsuke Aburaya, Tomoko Yamamoto Funazo, Koh Furugaki, Yasushi Yoshimura, Masatoshi Yamazoe, Hitomi Ajimizu, Yuto Yasuda, Takashi Nomizo, Hironori Yoshida, Yuichi Sakamori, Hiroaki Wake, Mitsuyoshi Ueda, Young Hak Kim and Toyohiro Hirai
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Takahiro Tsuji: Kyoto University
Hiroaki Ozasa: Kyoto University
Wataru Aoki: Kyoto University
Shunsuke Aburaya: Kyoto University
Tomoko Yamamoto Funazo: Kyoto University
Koh Furugaki: Chugai Pharmaceutical Co., Ltd
Yasushi Yoshimura: Chugai Pharmaceutical Co., Ltd
Masatoshi Yamazoe: Kyoto University
Hitomi Ajimizu: Kyoto University
Yuto Yasuda: Kyoto University
Takashi Nomizo: Kyoto University
Hironori Yoshida: Kyoto University
Yuichi Sakamori: Kyoto University
Hiroaki Wake: Kobe University
Mitsuyoshi Ueda: Kyoto University
Young Hak Kim: Kyoto University
Toyohiro Hirai: Kyoto University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-019-13771-5

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