Abstract LB-389: Antitumor activity of HM781–36B, a highly effective pan-HER inhibitor in erlotinib-resistant NSCLC and other EGFR-dependent cancer models
Authors: Cha Mi Young , Lee Kwang-Ok , Kim Young Hun , Suh Kwee Hyun , Park Seung Bum , Kim Maeng Sup , Lee Gwan Sun 
Published: August 2014

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. But clinical treatment is limited by the development of drug resistance resulting mainly from an acquired mutation (T790M). In this study, we evaluated the therapeutic potential of a novel, irreversible pan-HER inhibitor, HM781–36B. We demonstrated that HM781–36B is a potent EGFR inhibitor including the EGFR-acquired resistance mutation (IC50 4.2 nM in EGFR T790M and IC50 2.2 nM in EGFR L858R/T790M), as well as EGFR, HER-2 and HER-4 (IC50 3.2 nM, 5.3 nM and 23.5 nM, respectively), compared to other EGFR tyrosine kinases inhibitors (erlotinib, lapatinib and BIBW-2992), with kinase selectivity confirmed by 77 kinases panel assay except for Blk, Bmx and Btk. Strong growth inhibitory activity by the treatment of HM781–36B was confirmed with the range of IC50 0.6–6nM in NSCLC (HCC827, H358, H1975, Calu-3, and H1781), breast cancer (SK-Br3, BT474, MDA-175, and MDA-453), and gastric cancer (N87 and SNU-216) cell lines. HM781–36B showed 400–4,000 fold low growth inhibitory effect against normal cell lines (Hs-27 and Balb/c 3T3) relative to cancer cell lines. HM781–36B treatment results in the inhibition of EGFR phosphorylation and the subsequent deactivation of downstream signaling proteins in EGFR DelE746_A750-harboring erlotinib-sensitive HCC827 and EGFR L858R/T790M-harboring erlotinib-resistant NCI-H1975 NSCLC cells. HM781–36B interacts directly with its target enzyme (EGFR WT, EGFR T790M, HER-2), which was confirmed through prolongation study of phosphorylation inhibitory effect in A431 and SK-Br3 cells and direct fluorescence-based SDS-PAGE analysis by the incubation of Cy3-labeled HM781–36B probe. This irreversible occupation at the kinase domain leads to excellent in vivo efficacy of HM781–36B (1mg/kg – 5mg/kg) toward various xenograft models with EGFR-dependent cancers cells, including erlotinib-sensitive HCC827 NSCLC cells, erlotinib-resistant H1975 NSCLC cells, HER-2 overexpressing Calu-3 NSCLC cells, N87 gastric cancer cells, and SK-Ov3 ovarian cancer cells, and EGFR-overexpressing A431 epidermoid carcinoma cancer cells. On the basis of these preclinical results, HM781–36B was selected as a candidate for clinical development and a phase I study of HM781–36B is currently undergoing in South Korea.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-389. doi:10.1158/1538-7445.AM2011-LB-389