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- Title
HER3 activation contributes toward the emergence of ALK inhibitor-tolerant cells in ALK-rearranged lung cancer with mesenchymal features.
- Authors
Tanimura, Keiko; Yamada, Tadaaki; Okada, Koutaroh; Nakai, Kunihiro; Horinaka, Mano; Katayama, Yuki; Morimoto, Kenji; Ogura, Yuri; Takeda, Takayuki; Shiotsu, Shinsuke; Ichikawa, Kosuke; Watanabe, Satoshi; Morimoto, Yoshie; Iwasaku, Masahiro; Kaneko, Yoshiko; Uchino, Junji; Taniguchi, Hirokazu; Yoneda, Kazue; Matoba, Satoaki; Sakai, Toshiyuki
- 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.
- Subjects
ANAPLASTIC lymphoma kinase; LUNG cancer; ANAPLASTIC thyroid cancer; DISEASE relapse; KINASE inhibitors; CELL survival
- Publication
NPJ Precision Oncology, 2022, Vol 6, Issue 1, p1
- ISSN
2397-768X
- Publication type
Article
- DOI
10.1038/s41698-021-00250-8