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Cancer Res. 2017 May 15;77(10):2712-2721. doi: 10.1158/0008-5472.CAN-16-3404. Epub 2017 Mar 31.

Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors.

Author information

1
Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts.
2
Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts.
3
Department of Cancer Biology, Harvard Medical School, Boston, Massachusetts.
4
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
5
Lowe Center for Thoracic Oncology, Harvard Medical School, Boston, Massachusetts. pasi_janne@dfci.harvard.edu.
6
Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.

Abstract

Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20. Non-small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline-based inhibitors of EGFR or HER2, respectively. 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.

PMID:
28363995
PMCID:
PMC5596996
DOI:
10.1158/0008-5472.CAN-16-3404
[Indexed for MEDLINE]
Free PMC Article

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