HER3 activation contributes toward the emergence of ALK inhibitor-tolerant cells in ALK-rearranged lung cancer with mesenchymal features

Keiko Tanimura,Yoshiko Kaneko,Hisanori Uehara,Kazue Yoneda,Takayuki Takeda,Seiji Yano,Masahiro Iwasaku,Satoaki Matoba,Hirokazu Taniguchi,Satoshi Watanabe,Mano Horinaka,Shinsuke Shiotsu,Toshiyuki Sakai,Yoshie Morimoto,Junichi Uchino ,Kensuke Okada ,Tetsuro Kusaba,Yuki Katayama,Kosuke Ichikawa,Kenji Morimoto,Yuri Ogura,Kunihiro Nakai,Ryohei Katayama,Tadaaki Yamada,K Takayama

doi:10.1038/s41698-021-00250-8

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.

Highlights

Lung cancer is the leading cause of cancer-related death worldwide[1], with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all lung cancer cases[2]
In 2007, an echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was discovered in NSCLC5, and it has since been shown that approximately 3–5% of NSCLC patients harbor ALK-rearrangement and display dramatic responses to ALK-tyrosine kinase inhibitors (ALK-TKIs)[6,7]
Compared to their parental cells, these DT cells were cross-resistant to several ALK-TKIs and a larger population were in the G1 phase of the cell cycle, as reported previously[17] (Supplementary Fig. 1c)

Summary

Introduction

Lung cancer is the leading cause of cancer-related death worldwide[1], with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all lung cancer cases[2]. DT cells displayed increased E-cadherin and decreased vimentin expression compared with that of parental cells, suggesting that alectinib exposure promotes mesenchymal-to-epithelial transition (MET); these expressions levels were reversed under DF conditions for 9 days (Fig. 2b).

Results

Conclusion