A Novel HER2-Selective Kinase Inhibitor Is Effective in HER2 Mutant and Amplified Non-Small Cell Lung Cancer.

Abstract

In-frame insertions in exon 20 of HER2 are the most common HER2 mutations in patients with non-small cell lung cancer (NSCLC), a disease in which approved EGFR/HER2 tyrosine kinase inhibitors (TKI) display poor efficiency and undesirable side effects due to their strong inhibition of wild-type (WT) EGFR. Here, we report a HER2-selective covalent TKI, JBJ-08-178-01, that targets multiple HER2 activating mutations, including exon 20 insertions as well as amplification. JBJ-08-178-01 displayed strong selectivity toward HER2 mutants over WT EGFR compared with other EGFR/HER2 TKIs. Determination of the crystal structure of HER2 in complex with JBJ-08-178-01 suggests that an interaction between the inhibitor and Ser783 may be responsible for HER2 selectivity. The compound showed strong antitumoral activity in HER2-mutant or amplified cancers in vitro and in vivo. Treatment with JBJ-08-178-01 also led to a reduction in total HER2 by promoting proteasomal degradation of the receptor. Taken together, the dual activity of JBJ-08-178-01 as a selective inhibitor and destabilizer of HER2 represents a combination that may lead to better efficacy and tolerance in patients with NSCLC harboring HER2 genetic alterations or amplification.

SIGNIFICANCE:

This study describes unique mechanisms of action of a new mutant-selective HER2 kinase inhibitor that reduces both kinase activity and protein levels of HER2 in lung cancer.

• Authors: Jieun Son, Jaebong Jang, Tyler S Beyett, Yoonji Eum, Heidi M Haikala, Alyssa Verano, Mika Lin, John M Hatcher, Nicholas P Kwiatkowski, Pinar Ö Eser, Michael J Poitras, Stephen Wang, Man Xu, Prafulla C Gokhale, Michael D Cameron, Michael J Eck, Nathanael S Gray, Pasi A Jänne
• Journal: Cancer research (Cancer Res) Vol. 82 Issue 8 Pg. 1633-1645 (04 15 2022) ISSN: 1538-7445 [Electronic] United States
• PMID: 35149586 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Receptor, ErbB-2

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Exons
• Humans
• Lung Neoplasms (chemically induced, drug therapy, genetics)
• Mutation
• Protein Kinase Inhibitors (adverse effects)
• Receptor, ErbB-2 (metabolism)