Reference Detail

Ref Type Journal Article
PMID (28363995)
Authors Kosaka T, Tanizaki J, Paranal RM, Endoh H, Lydon C, Capelletti M, Repellin CE, Choi J, Ogino A, Calles A, Ercan D, Redig AJ, Bahcall M, Oxnard GR, Eck MJ, Jänne PA
Title Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors.
Journal Cancer research
Vol 77
Issue 10
Date 2017 May 15
URL
Abstract Text 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.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
A767_V769dup duplication gain of function EGFR A767_V769dup (also referred to as V769_D770insASV) indicates the insertion of 3 duplicate amino acids, alanine (A)-767 through valine (V)-769, in the protein kinase domain of the Egfr protein (UniProt.org). A767_V769dup results in constitutive Egfr phosphorylation, downstream signaling activation, and transformation of cultured cells (PMID: 24353160, PMID: 28363995).
D770delinsGY indel gain of function EGFR D770delinsGY results in a deletion of aspartic acid (D) at amino acid 770 within the protein kinase domain of the Egfr protein, combined with the insertion of a glycine (G) and a tyrosine (Y) at the same site (UniProt.org). D770delinsGY results in autophosphorylation of Egfr, transformation of cultured cells, and is associated with resistance to some Egfr inhibitors (PMID: 28363995). Y
exon 20 ins insertion gain of function EGFR exon 20 insertions are in-frame insertions within the kinase domain of Egfr (PMID: 17318210). Exon 20 insertions result in increased Egfr kinase activity, and are associated with low sensitivity to Egfr tyrosine kinase inhibitors (PMID: 17318210, PMID: 24353160, PMID: 28363995).
C805S missense unknown ERBB2 (HER2) C805S lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). C805S is associated with resistance to Erbb2 (Her2)-targeted therapies in cell culture (PMID: 28363995), but has not been biochemically characterized and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2019). Y
G778_S779insCPG insertion gain of function - predicted ERBB2 (HER2) G778_S779insCPG results in the insertion of three amino acids in the protein kinase domain of the Erbb2 (Her2) protein between amino acids 778 and 779 (UniProt.org). G778_S779insCPG is transforming in culture (PMID: 28363995), and based on the effects of other ERBB2 (HER2) exon 20 insertions (PMID: 16843263, PMID: 17311002), is predicted to result in a gain of Erbb2 (Her2) function.
M774delinsWLV indel gain of function ERBB2 (HER2) M774delinsWLV results in a deletion of methionine (M) at amino acid 774 within the protein kinase domain of the Erbb2 (Her2) protein, combined with the insertion of a tryptophan (W), lysine (L), and a valine (V) at the same site (UniProt.org). M774delinsWLV results in activation of Erbb2 (Her2) and transformation of cultured cells (PMID: 28363995).
P780_Y781insGSP insertion gain of function ERBB2 (HER2) P780_Y781insGSP (also referred to as G778_P780dup) results in the insertion of three amino acids in the protein kinase domain of the Erbb2 (Her2) protein between amino acids 780 and 781 (UniProt.org). P780_Y781insGSP results in constitutive activation of Erbb2 (Her2), increased downstream signaling, and is transforming in cell culture (PMID: 23220880, PMID: 28363995, PMID: 29967253).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 M774delinsWLV Advanced Solid Tumor sensitive Dacomitinib Preclinical - Cell culture Actionable In a preclinical study, Vizimpro (dacomitinib) inhibited growth of transformed cells expressing ERBB2 (HER2) M774delinsWLV in culture (PMID: 28363995). 28363995
ERBB2 G778_P780dup Advanced Solid Tumor conflicting Neratinib Preclinical - Cell culture Actionable In a preclinical study, Nerlynx (neratinib) inhibited growth of transformed cells expressing ERBB2 (HER2) G778_P780dup (also referred to as P780_Y781insGSP) in culture (PMID: 28363995). 28363995
EGFR D770delinsGY EGFR C797S Advanced Solid Tumor resistant Dacomitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing an EGFR D770delinsGY and EGFR C797S double mutation demonstrated resistance to Vizimpro (dacomitinib) in culture (PMID: 28363995). 28363995
EGFR N771_H773dup lung adenocarcinoma sensitive Afatinib Preclinical - Patient cell culture Actionable In a preclinical study, Gilotrif (afatinib) inhibited EGFR phosphorylation and growth of a patient-derived lung adenocarcinoma cell line harboring EGFR N771_H773dup (also referred to as H773_V774insNPH) in culture (PMID: 28363995). 28363995
ERBB2 Y772_A775dup ERBB2 C805S Advanced Solid Tumor resistant Dacomitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing ERBB2 (HER2) C805S and ERBB2 (HER2) Y772_A775dup (also referred to as A775_G776insYVMA) demonstrated resistance to Vizimpro (dacomitinib) in culture (PMID: 28363995). 28363995
EGFR P772_H773insPNP lung adenocarcinoma sensitive Dacomitinib Preclinical - Patient cell culture Actionable In a preclinical study, Vizimpro (dacomitinib) inhibited EGFR phosphorylation and growth of a patient-derived lung adenocarcinoma cell line harboring EGFR P772_H773insPNP in culture (PMID: 28363995). 28363995
EGFR P772_H773insPNP lung adenocarcinoma sensitive Afatinib Preclinical - Patient cell culture Actionable In a preclinical study, Gilotrif (afatinib) inhibited EGFR phosphorylation and growth of a patient-derived lung adenocarcinoma cell line harboring EGFR P772_H773insPNP in culture (PMID: 28363995). 28363995
ERBB2 Y772_A775dup ERBB2 C805S Advanced Solid Tumor resistant Afatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing ERBB2 (HER2) Y772_A775dup (also referred to as A775_G776insYVMA) and ERBB2 (HER2) C805S demonstrated resistance to Gilotrif (afatinib) in culture (PMID: 28363995). 28363995
ERBB2 G778_S779insCPG Advanced Solid Tumor sensitive Dacomitinib Preclinical - Cell culture Actionable In a preclinical study, Vizimpro (dacomitinib) inhibited growth of transformed cells expressing ERBB2 (HER2) G778_S779insCPG in culture (PMID: 28363995). 28363995
EGFR A767_V769dup Advanced Solid Tumor resistant Dacomitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EGFR A767_V769dup (also referred to as V769_D770insASV) demonstrated resistance to Vizimpro (dacomitinib) in culture (PMID: 28363995). 28363995
EGFR D770delinsGY EGFR C797S Advanced Solid Tumor sensitive Afatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing an EGFR D770delinsGY/EGFR C797S double mutation demonstrated resistance to Gilotrif (afatinib) in culture (PMID: 28363995). 28363995
ERBB2 G778_P780dup lung adenocarcinoma predicted - sensitive Afatinib Case Reports/Case Series Actionable In a clinical case study, a patient with metastatic lung adenocarcinoma harboring ERBB2 (HER2) G778_P780dup (also referred to as V777_G778insGSP) demonstrated tumor shrinkage and clinical response for 7 months following treatment with Gilotrif (afatinib) (PMID: 28363995). 28363995
ERBB2 M774delinsWLV ERBB2 C805S Advanced Solid Tumor resistant Afatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing ERBB2 (HER2) M774delinsWLV and ERBB2 (HER2) C805S demonstrated resistance to Gilotrif (afatinib) in culture (PMID: 28363995). 28363995
ERBB2 M774delinsWLV ERBB2 C805S Advanced Solid Tumor resistant Neratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing ERBB2 (HER2) M774delinsWLV and ERBB2 (HER2) C805S demonstrated resistance to Nerlynx (neratinib) in culture (PMID: 28363995). 28363995
EGFR D770delinsGY Advanced Solid Tumor resistant Neratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EGFR D770delinsGY demonstrated resistance to Nerlynx (neratinib) in culture (PMID: 28363995). 28363995
EGFR D770delinsGY Advanced Solid Tumor sensitive Dacomitinib Preclinical - Cell culture Actionable In a preclinical study, Vizimpro (dacomitinib) inhibited EGFR phosphorylation and growth of transformed cells expressing EGFR D770delinsGY in culture (PMID: 28363995). 28363995
EGFR Y764_V765insHH Advanced Solid Tumor resistant Dacomitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EGFR Y764_V765insHH demonstrated resistance to Vizimpro (dacomitinib) in culture (PMID: 28363995). 28363995
EGFR S768_D770dup Advanced Solid Tumor resistant Dacomitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing EGFR S768_D770dup (also referred to as D770_N771insSVD) demonstrated resistance to Vizimpro (dacomitinib) in culture (PMID: 28363995). 28363995
ERBB2 Y772_A775dup ERBB2 C805S Advanced Solid Tumor resistant Neratinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells co-expressing ERBB2 (HER2) Y772_A775dup (also referred to as A775_G776insYVMA) and ERBB2 (HER2) C805S demonstrated resistance to Nerlynx (neratinib) in culture (PMID: 28363995). 28363995
EGFR D770delinsGY EGFR T790M Advanced Solid Tumor resistant Dacomitinib Preclinical - Cell culture Actionable In a preclinical study, acquisition of EGFR T790M was associated with resistance to Vizimpro (dacomitinib) in transformed cells expressing EGFR D770delinsGY (PMID: 28363995). 28363995
ERBB2 G778_P780dup Advanced Solid Tumor sensitive Dacomitinib Preclinical - Cell culture Actionable In a preclinical study, Vizimpro (dacomitinib) inhibited growth of transformed cells expressing ERBB2 (HER2) G778_P780dup (also referred to as P780_Y781insGSP) in culture (PMID: 28363995). 28363995
EGFR N771_H773dup lung adenocarcinoma sensitive Dacomitinib Preclinical - Patient cell culture Actionable In a preclinical study, Vizimpro (dacomitinib) inhibited EGFR phosphorylation and growth of a patient-derived lung adenocarcinoma cell line harboring EGFR N771_H773dup (also referred to as H773_V774insNPH) in culture (PMID: 28363995). 28363995
ERBB2 Y772_A775dup Advanced Solid Tumor sensitive Neratinib Preclinical - Cell culture Actionable In a preclinical study, Nerlynx (neratinib) inhibited growth of transformed cells expressing ERBB2 (HER2) Y772_A775dup (also referred to as ERBB2 A775_G776insYVMA) in culture (PMID: 28363995). 28363995
EGFR D770delinsGY EGFR T790M Advanced Solid Tumor sensitive Afatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing an EGFR D770delinsGY/EGFR T790M double mutation demonstrated resistance to Gilotrif (afatinib) in culture (PMID: 28363995). 28363995
ERBB2 M774delinsWLV ERBB2 C805S Advanced Solid Tumor resistant Dacomitinib Preclinical - Cell culture Actionable In a preclinical study, acquisition of ERBB2 (HER2) C805S in transformed cells expressing ERBB2 (HER2) M774delinsWLV conferred resistance to Vizimpro (dacomitinib) in culture (PMID: 28363995). 28363995