Article

CHMFL-26 is a highly potent irreversible HER2 inhibitor for use in the treatment of HER2-positive and HER2-mutant cancers

Jiang-yan Cao1,2, Shuang Qi1,3, Hong Wu1,3, Ao-li Wang1,3, Qing-wang Liu1,3, Xi-xiang Li1,3, Bei-lei Wang1,3, Juan Ge1,2, Feng-ming Zou1,3, Cheng Chen1, Jun-jie Wang1,2, Chen Hu1,3, Jing Liu1,3, Wen-chao Wang1,3, Qing-song Liu1,2,3,4
1 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
2 University of Science and Technology of China, Hefei 230026, China
3 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230031, China
4 Precision Medicine Research Laboratory of Anhui Province, Hefei 230088, China
Correspondence to: Jing Liu: jingliu@hmfl.ac.cn, Wen-chao Wang: wwcbox@hmfl.ac.cn, Qing-song Liu: qsliu97@hmfl.ac.cn,
DOI: 10.1038/s41401-022-00882-x
Received: 6 October 2021
Accepted: 27 January 2022
Advance online: 28 February 2022

Abstract

Oncogene HER2 is amplified in 20%–25% of human breast cancers and 6.1%–23.0% of gastric cancers, and HER2-directed therapy significantly improves the outcome for patients with HER2-positive cancers. However, drug resistance is still a clinical challenge due to primary or acquired mutations and drug-induced negative regulatory feedback. In this study, we discovered a potent irreversible HER2 kinase inhibitor, CHMFL-26, which covalently targeted cysteine 805 of HER2 and effectively overcame the drug resistance caused by HER2 V777L, HER2 L755S, HER2 exon 20 insertions, and p95-HER2 truncation mutations. CHMFL-26 displayed potent antiproliferation efficacy against HER2-amplified and mutant cells through constant HER2-mediated signaling pathway inhibition and apoptosis induction. In addition, CHMFL-26 suppressed tumor growth in a dose-dependent manner in xenograft mouse models. Together, these results suggest that CHMFL-26 may be a potential novel anti-HER2 agent for overcoming drug resistance in HER2-positive cancer therapy.
Keywords: HER2; breast cancers; gastric cancers; irreversible inhibitor; drug resistance

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