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      Response heterogeneity of EGFR and HER2 exon 20 insertions to covalent EGFR and HER2 inhibitors

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          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 a 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.

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          Author and article information

          Journal
          2984705R
          2786
          Cancer Res
          Cancer Res.
          Cancer research
          0008-5472
          1538-7445
          18 August 2017
          31 March 2017
          15 May 2017
          15 November 2017
          : 77
          : 10
          : 2712-2721
          Affiliations
          [1 ]Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115 USA
          [2 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115 USA
          [3 ]Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115 USA
          [4 ]Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 USA
          [5 ]Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02115 USA
          Author notes
          [# ]Address correspondence to: Pasi A. Jänne, MD, PhD, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, LC-4114, Boston, MA, 02215, Phone: (617) 632-6076, Fax: (617) 582-7683, pasi_janne@ 123456dfci.harvard.edu
          Article
          PMC5596996 PMC5596996 5596996 nihpa862742
          10.1158/0008-5472.CAN-16-3404
          5596996
          28363995
          086d4ed2-acca-40ae-a5cb-a34bfeeb2b4d
          History
          Categories
          Article

          Epidermal growth factor receptor,human epidermal growth factor receptor 2,exon 20,drug resistance,tyrosine kinase inhibitor

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