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. READ ARTICLE
Precision Oncology DOI:10.1038/s41698-021-00250-8
Authors: 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
