Missing content? – Request curation!
Request curation for specific Genes, variants, or PubMed publications.
Have questions, comments or suggestions? - Let us know!
Email us at : ckbsupport@jax.org
Ref Type | Journal Article |
PMID | (26545934) |
Authors | Suzawa K, Toyooka S, Sakaguchi M, Morita M, Yamamoto H, Tomida S, Ohtsuka T, Watanabe M, Hashida S, Maki Y, Soh J, Asano H, Tsukuda K, Miyoshi S |
Title | Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations. |
Journal | Cancer science |
Vol | 107 |
Issue | 1 |
Date | 2016 Jan |
URL | |
Abstract Text | Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G1 arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations. |
Molecular Profile | Treatment Approach |
---|
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 |
---|
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
---|---|---|---|---|---|
ERBB2 | G660D | missense | gain of function | ERBB2 (HER2) G660D lies within the transmembrane domain of the Erbb2 (Her2) protein (PMID: 30449325). G660D leads to constitutive activation of Erbb2 (Her2) and increased downstream signaling in cell culture (PMID: 26545934) and results in increased cell survival and the formation of multi-acinar bodies in the absence of ligand (PMID: 30449325). | |
ERBB2 | G776delinsLC | indel | gain of function | ERBB2 (HER2) G776delinsLC results in a deletion of a glycine (G) at amino acid 776 within the protein kinase domain of the Erbb2 (Her2) protein, combined with the insertion of a leucine (L) and a cystine (C) at the same site (UniProt.org). G776delinsLC leads to constitutive activation of Erbb2 (Her2), increased downstream signaling, is transforming in cell culture (PMID: 26545934, PMID: 29967253, PMID: 31588020), and confers resistance to selected tyrosine kinase inhibitors (PMID: 31588020). | Y |
ERBB2 | G776delinsVC | indel | gain of function | ERBB2 (HER2) G776delinsVC results in a deletion of a glycine (G) at amino acid 776 within the protein kinase domain of the Erbb2 (Her2) protein, combined with the insertion of a valine (V) and a cystine (C) at the same site (UniProt.org). G776delinsVC leads to constitutive activation of Erbb2 (Her2), increased downstream signaling (PMID: 26545934, PMID: 31588020), is transforming in cell culture (PMID: 29533785, PMID: 29967253), and confers resistance to selected tyrosine kinase inhibitors (PMID: 31588020). | Y |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
ERBB2 G776delinsVC | lung non-small cell carcinoma | conflicting | Afatinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Gilotrif (afatinib) inhibited proliferation and induced cell-cycle arrest and apoptosis of a non-small cell lung cancer (NSCLC) cell line harboring ERBB2 (HER2) G776delinsVC in culture and inhibited tumor growth in NSCLC cell line xenografts carrying ERBB2 (HER2) G776delinsVC (PMID: 26545934). | 26545934 |
ERBB2 G778_P780dup | lung cancer | sensitive | Afatinib | Preclinical | Actionable | In a preclinical study, Gilotrif (afatinib) inhibited Erbb2 (Her2) phosphorylation and downstream signaling in bronchial epithelial cells expressing ERBB2 (HER2) G778_P780dup (also referred to as P780_Y781insGSP) in culture (PMID: 26545934). | 26545934 |
ERBB2 Y772_A775dup | lung cancer | no benefit | Gefitinib | Preclinical | Actionable | In a preclinical study, bronchial epithelial cells expressing ERBB2 (HER2) Y772_A775dup (also referred to as A775_G776insYVMA) did not demonstrate sensitivity to Iressa (gefitinib) in culture (PMID: 26545934). | 26545934 |
ERBB2 G776delinsLC | lung cancer | no benefit | Gefitinib | Preclinical | Actionable | In a preclinical study, bronchial epithelial cells expressing ERBB2 (HER2) G776delinsLC did not demonstrate sensitivity to Iressa (gefitinib) in culture (PMID: 26545934). | 26545934 |
ERBB2 G776delinsVC | lung cancer | sensitive | Afatinib | Preclinical | Actionable | In a preclinical study, Gilotrif (afatinib) inhibited Erbb2 (Her2) phosphorylation and downstream signaling in bronchial epithelial cells expressing ERBB2 (HER2) G776delinsVC in culture (PMID: 26545934). | 26545934 |
ERBB2 G776delinsVC | lung cancer | no benefit | Gefitinib | Preclinical | Actionable | In a preclinical study, bronchial epithelial cells expressing ERBB2 (HER2) G776delinsVC did not demonstrate sensitivity to Iressa (gefitinib) in culture (PMID: 26545934). | 26545934 |
ERBB2 G776delinsVC | lung non-small cell carcinoma | resistant | Gefitinib | Preclinical | Actionable | In a preclinical study, non-small cell lung cancer cells harboring ERBB2 (HER2) G776delinsVC demonstrated resistance to treatment with Iressa (gefitinib) in culture (PMID: 26545934). | 26545934 |
ERBB2 Y772_A775dup | lung cancer | sensitive | Afatinib | Preclinical | Actionable | In a preclinical study, Gilotrif (afatinib) inhibited Erbb2 (Her2) phosphorylation and downstream signaling in bronchial epithelial cells expressing ERBB2 (HER2) Y772_A775dup (also referred to as A775_G776insYVMA) in culture (PMID: 26545934). | 26545934 |
ERBB2 amp | breast cancer | sensitive | Afatinib | Preclinical | Actionable | In a preclinical study, Gilotrif (afatinib) inhibited proliferation of breast cancer cell lines with ERBB2 (HER2) amplification in culture (PMID: 26545934). | 26545934 |
ERBB2 G776delinsLC | lung cancer | sensitive | Afatinib | Preclinical | Actionable | In a preclinical study, Gilotrif (afatinib) inhibited Erbb2 (Her2) phosphorylation and downstream signaling in bronchial epithelial cells expressing ERBB2 (HER2) G776delinsLC in culture (PMID: 26545934). | 26545934 |
ERBB2 V659E | lung cancer | no benefit | Gefitinib | Preclinical | Actionable | In a preclinical study, bronchial epithelial cells expressing ERBB2 (HER2) V659E did not demonstrate sensitivity to Iressa (gefitinib) in culture (PMID: 26545934). | 26545934 |
ERBB2 G778_P780dup | lung cancer | no benefit | Gefitinib | Preclinical | Actionable | In a preclinical study, bronchial epithelial cells expressing ERBB2 (HER2) G778_P780dup (also referred to as P780_Y781insGSP) did not demonstrate sensitivity to Iressa (gefitinib) in culture (PMID: 26545934). | 26545934 |
ERBB2 amp | lung non-small cell carcinoma | sensitive | Afatinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Gilotrif (afatinib) inhibited proliferation and induced cell-cycle arrest and apoptosis of non-small cell lung cancer (NSCLC) cell lines with ERBB2 (HER2) amplification in culture, and inhibited tumor growth in ERBB2 (HER2)-amplified NSCLC cell line xenograft models (PMID: 26545934). | 26545934 |
ERBB2 V659E | lung cancer | sensitive | Afatinib | Preclinical | Actionable | In a preclinical study, Gilotrif (afatinib) inhibited Erbb2 (Her2) phosphorylation and downstream signaling in bronchial epithelial cells expressing ERBB2 (HER2) V659E in culture (PMID: 26545934). | 26545934 |
ERBB2 amp | lung squamous cell carcinoma | resistant | Gefitinib | Preclinical | Actionable | In a preclinical study, a lung squamous cell carcinoma cell line with ERBB2 (HER2) amplification demonstrated resistance to treatment with Iressa (gefitinib) in culture (PMID: 26545934). | 26545934 |
ERBB2 G660D | lung cancer | sensitive | Afatinib | Preclinical | Actionable | In a preclinical study, Gilotrif (afatinib) inhibited Erbb2 (Her2) phosphorylation and downstream signaling in bronchial epithelial cells expressing ERBB2 (HER2) G660D in culture (PMID: 26545934). | 26545934 |
ERBB2 G660D | lung cancer | no benefit | Gefitinib | Preclinical | Actionable | In a preclinical study, bronchial epithelial cells cells expressing ERBB2 (HER2) G660D did not demonstrate sensitivity to Iressa (gefitinib) in culture (PMID: 26545934). | 26545934 |