Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors
In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these findings, we used afatinib to treat an NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable partial response. We further identified secondary mutations in EGFR (T790M or C797S) and HER2 (C805S) that mediated acquired drug resistance in drug-sensitive EGFR or HER2 exon 20 insertion models. Overall, our findings identified a subset of EGFR and HER2 exon 20 insertion mutations that are sensitive to existing covalent quinazoline–based EGFR/HER2 inhibitors, with implications for current clinical treatment and next-generation small-molecule inhibitors. Cancer Res; 77(10); 2712–21. ©2017 AACR.
Source: Cancer Research - Category: Cancer & Oncology Authors: Takayuki Kosaka, Junko Tanizaki, Raymond M. Paranal, Hideki Endoh, Christine Lydon, Marzia Capelletti, Claire E. Repellin, Jihyun Choi, Atsuko Ogino, Antonio Calles, Dalia Ercan, Amanda J. Redig, Magda Bahcall, Geoffrey R. Oxnard, Michael J. Eck, Pasi A. Tags: Therapeutics, Targets, and Chemical Biology Source Type: research
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