STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis

被引：0
作者：
Naohiro Yanagimura
Shinji Takeuchi
Koji Fukuda
Sachiko Arai
Azusa Tanimoto
Akihiro Nishiyama
Naohisa Ogo
Hiroyuki Takahashi
Akira Asai
Satoshi Watanabe
Toshiaki Kikuchi
Seiji Yano
机构：
[1] Kanazawa University,Division of Medical Oncology Cancer Research Institute
[2] Niigata University Graduate School of Medical and Dental Sciences,Department of Respiratory Medicine and Infectious Diseases
[3] Kanazawa University,Nano Life Science Institute
[4] University of Shizuoka,Center for Drug Discovery, Graduate School of Pharmaceutical Sciences
[5] Yakult Honsha Co. Ltd,Pharmaceutical Business Division
来源：
npj Precision Oncology | / 6卷
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摘要：
Patients with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who are prescribed ALK-tyrosine kinase inhibitors (ALK-TKIs) rarely have complete responses, with residual tumors relapsing as heterogeneous resistant phenotypes. Herein, we investigated new therapeutic strategies to reduce and eliminate residual tumors in the early treatment phase. Functional genomic screening using small guide RNA libraries showed that treatment-induced adaptive survival of ALK-rearranged lung cancer cells was predominantly dependent on STAT3 activity upon ALK inhibition. STAT3 inhibition effectively suppressed the adaptive survival of ALK-rearranged lung cancer cells by enhancing ALK inhibition-induced apoptosis. The combined effects were characterized by treatment-induced STAT3 dependence and transcriptional regulation of anti-apoptotic factor BCL-XL. In xenograft study, the combination of YHO-1701 (STAT3 inhibitor) and alectinib significantly suppressed tumor regrowth after treatment cessation with near tumor remission compared with alectinib alone. Hence, this study provides new insights into combined therapeutic strategies for patients with ALK-rearranged lung cancer.
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