학술논문
HER3 activation contributes toward the emergence of ALK inhibitor-tolerant cells in ALK-rearranged lung cancer with mesenchymal features
Document Type
article
Author
Keiko Tanimura; Tadaaki Yamada; Koutaroh Okada; Kunihiro Nakai; Mano Horinaka; Yuki Katayama; Kenji Morimoto; Yuri Ogura; Takayuki Takeda; Shinsuke Shiotsu; Kosuke Ichikawa; Satoshi Watanabe; Yoshie Morimoto; Masahiro Iwasaku; Yoshiko Kaneko; Junji Uchino; Hirokazu Taniguchi; Kazue Yoneda; Satoaki Matoba; Toshiyuki Sakai; Hisanori Uehara; Seiji Yano; Tetsuro Kusaba; Ryohei Katayama; Koichi Takayama
Source
npj Precision Oncology, Vol 6, Iss 1, Pp 1-12 (2022)
Subject
Language
English
ISSN
2397-768X
Abstract
Abstract Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare. Here, we investigated the molecular mechanisms underlying the emergence and maintenance of drug-tolerant cells in ALK-rearranged lung cancer. Cell based-assays demonstrated that HER3 activation and mesenchymal-to-epithelial transition, mediated through ZEB1 proteins, help maintain cell survival and induce the emergence of ALK-TKI-tolerant cells. Compared with ALK-TKIs alone, cotreatment with pan-HER inhibitor afatinib and ALK-TKIs prevented tumor regrowth, leading to the eradication of tumors in ALK-rearranged tumors with mesenchymal features. Moreover, pre-treatment vimentin expression in clinical specimens obtained from patients with ALK-rearranged lung cancer was associated with poor ALK-TKI treatment outcomes. These results demonstrated that HER3 activation plays a pivotal role in the emergence of ALK-TKI-tolerant cells. Furthermore, the inhibition of HER3 signals combined with ALK-TKIs dramatically improves treatment outcomes for ALK-rearranged lung cancer with mesenchymal features.