@article{95c8d78a8e494a938545751a756e34f7,
title = "Pan-HER inhibitors overcome lorlatinib resistance caused by NRG1/HER3 activation in ALK-rearranged lung cancer",
abstract = "Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) with a broad coverage against ALK mutations, has demonstrated dramatic effects in patients with ALK-rearranged lung cancer. The mechanisms of acquired resistance to lorlatinib by secondary ALK compound mutations have recently been reported; however, resistance mechanisms other than secondary mutations remain unclear. Here, we investigated the molecular mechanisms of the acquired resistance in ALK-rearranged lung cancer cells in vitro. We established two different lorlatinib-resistant ALK-rearranged lung cancer cell lines (H3122LR and A925LLR) via long-term administration of lorlatinib. These resistant cells did not harbor the secondary ALK mutations and showed cross-resistance to the other kinds of ALK-TKIs (crizotinib or alectinib) compared with the parental cells; however, these resistant cells overexpressed the phosphorylated human epidermal growth factor receptor 3 (HER3) protein and the ligand of HER3 (neuregulin 1; NRG1). Pharmacological inhibition of HER3 with pan-HER inhibitors or genetic knockdown of HER3 with siRNA resensitized H3122LR and A925LLR cells to lorlatinib in vitro, indicating that H3122LR and A925LLR acquired resistance by NRG1/HER3 activation. These findings demonstrated that targeting NRG1/HER3 is a potential novel therapeutic option for lorlatinib-resistant ALK-rearranged lung cancer.",
keywords = "ALK inhibitor, HER3, drug resistance, lorlatinib, non–small-cell lung cancer",
author = "Hirokazu Taniguchi and Kazumasa Akagi and Yosuke Dotsu and Tadaaki Yamada and Sawana Ono and Erika Imamura and Hiroshi Gyotoku and Shinnosuke Takemoto and Hiroyuki Yamaguchi and Triparna Sen and Seiji Yano and Hiroshi Mukae",
note = "Funding Information: HY received commercial research grants from Boehringer‐Ingelheim and received speaking honoraria from Pfizer, Chugai Pharmaceutical, and Boehringer‐Ingelheim. TY received commercial research grants from Pfizer, Ono Pharmaceutical, Chugai Pharmaceutical, Janssen, and Takeda Pharmaceutical, and received speaking honoraria from Eli Lilly. SY received commercial research grants from Chugai Pharmaceutical, Takeda Pharmaceutical, and Boehringer‐Ingelheim, and received speaking honoraria from Chugai Pharmaceutical, Boehringer‐Ingelheim, Takeda Pharmaceutical, and Pfizer. SY is an editorial board member of Cancer Science. HM received commercial research grants from Boehringer‐Ingelheim, received speaking honoraria from Pfizer, Chugai Pharmaceutical, and Boehringer‐Ingelheim, and annual remuneration from Pfizer as an adviser. The remaining authors have no conflict of interest. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication. Funding Information: We thank Dr. Fumihiro Tanaka and Dr. Hidetaka Uramoto (the Second Department of Surgery, University of Occupational and Environmental Health, Japan) for kindly providing A925L cells. We would like to thank Ms. Emi Saito, Ms. Emi Yoshitake (Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences), Dr. Azusa Tanimoto, Ms. Sachiko Arai (Cancer Research Institute, Kanazawa University), Dr. Charles M. Rudin (Department of Medicine, Memorial Sloan Kettering Cancer Center) for their technical assistance and fruitful discussions. We thank RIKEN GENESIS (Kanagawa, Japan) for the examination of whole exome sequence. Images for the graphical abstract (Figure 6) were created with BioRender.com. Funding Information: This work was supported by research grants from a Non‐Profit Organization aimed to Support Community Medicine Research in Nagasaki (to HT) and Joint Research with the Cancer Research Institute of Kanazawa University (to HT). Publisher Copyright: {\textcopyright} 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.",
year = "2023",
month = jan,
doi = "10.1111/cas.15579",
language = "English",
volume = "114",
pages = "164--173",
journal = "Cancer Science",
issn = "1347-9032",
publisher = "Wiley-Blackwell",
number = "1",
}