A novel HER2-selective kinase inhibitor is effective in HER2 mutant and amplified non-small cell lung cancer

In-frame insertions in exon 20 of human epidermal growth factor receptor-2 (HER2) are the most common HER2 mutations in non-small cell lung cancer (NSCLC) patients, a disease in which approved EGFR/HER2 tyrosine kinase inhibitors (TKIs) display poor efficiency and undesirable side effects due to their strong inhibition of wild-type 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 towards HER2 mutants over wild-type 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 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 which may lead to better efficacy and tolerance in NSCLC patients harboring HER2 genetic alterations or amplification.