Antitumor activity of HM781‐36B, a highly effective pan‐HER inhibitor in erlotinib‐resistant NSCLC and other EGFR‐dependent cancer models

Abstract The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases has been implicated in a variety of cancers. In particular, activating mutations such as the L858R point mutation in exon 21 and the small in‐frame deletions in exon 19 of the EGFR tyrosine kinase domain are correlated with sensitivity to EGFR tyrosine kinase inhibitors in non‐small cell lung cancer (NSCLC) patients. Clinical treatment of patients is limited by the development of drug resistance resulting mainly from a gatekeeper mutation (T790M). In this study, we evaluated the therapeutic potential of a novel, irreversible pan‐HER inhibitor, HM781‐36B. The results from this study show that HM781‐36B is a potent inhibitor of EGFR in vitro , including the EGFR ‐acquired resistance mutation (T790M), as well as HER‐2 and HER‐4, compared with other EGFR tyrosine kinases inhibitors (erlotinib, lapatinib and BIBW2992). HM781‐36B treatment of EGFR DelE746_A750‐harboring erlotinib‐sensitive HCC827 and EGFR L858R/T790M‐harboring erlotinib‐resistant NCI‐H1975 NSCLC cells results in the inhibition of EGFR phosphorylation and the subsequent deactivation of downstream signaling proteins. Additionally, HM781‐36B shows an excellent efficacy in a variety of EGFR‐ and HER‐2‐dependent tumor xenograft models, including erlotinib‐sensitive HCC827 NSCLC cells, erlotinib‐resistant NCI‐H1975 NSCLC cells, HER‐2 overexpressing Calu‐3 NSCLC cells, NCI‐N87 gastric cancer cells, SK‐Ov3 ovarian cancer cells and EGFR‐overexpressing A431 epidermoid carcinoma cancer cells. On the basis of these preclinical results, HM781‐36B is the most potent pan‐HER inhibitor, which will be advantageous for the treatment of patients with NSCLC including clinical limitation caused by acquired mutation ( EGFR T790M), breast cancer and gastric cancer.