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Ref Type Journal Article
PMID (32036069)
Authors Zhao S, Fang W, Pan H, Yang Y, Liang Y, Yang L, Dong X, Zhan J, Wang K, Zhang L
Title Conformational Landscapes of HER2 Exon 20 Insertions Explain Their Sensitivity to Kinase Inhibitors in Lung Adenocarcinoma.
Journal Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
Vol 15
Issue 6
Date 2020 Jun
URL
Abstract Text HER2 exon 20 insertion (ex20ins) is one of the most intractable problems in lung cancer. Most ex20ins are resistant to available EGFR or pan-HER tyrosine kinase inhibitors (TKIs), with the exception of a few mutants. However, the mechanism for TKI response and resistance of HER2 ex20ins remains poorly understood.Next-generation sequencing-based genomic profiling data of 4139 patients with lung cancer were interrogated for HER2 ex20ins. Structural modeling and molecular dynamics simulations of common HER2 ex20ins were carried out to provide insights into the mechanism of activation and response heterogeneity of ex20ins. Molecular docking was performed to predict affinity to TKIs. Therapeutic decisions for patients were made on the basis of the results of genomic profiling.From 155 HER2-mutant lung cancer cases, Y772_A775dup and G778_P780dup were identified in 74 (47.7%) and 18 (11.6%) cases, respectively. Molecular dynamics simulations revealed that HER2 ex20ins led to ligand-independent kinase activation by changing the conformational landscape of HER2 kinase and restricting kinase conformation in the active state. G778_P780dup had a three-amino acid extension in the αC-β4 loop and retained the HER2-characteristic G776 and G778. Compared with Y772_A775dup, it had less restriction on kinase conformational sampling and higher affinity to afatinib, dacomitinib, pyrotinib, and poziotinib. Treating lung adenocarcinomas carrying G778_P780dup with these inhibitors led to sustained tumor responses in six of the 10 patients.The kinase conformational landscape dictated by the length of the αC-β4 loop and residues at HER2 776 and 778 position explains TKI sensitivity in ex20ins. This finding could guide therapeutic decisions with currently available therapies and future drug development strategies.

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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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 G778_P780dup ERBB2 amp lung adenocarcinoma predicted - sensitive Dacomitinib Case Reports/Case Series Actionable In a clinical case study, a patient with metastatic lung adenocarcinoma harboring ERBB2 (HER2) G778_P780dup (also reported as P780_Y781insGSP) demonstrated an ongoing partial response following four months of Vizimpro (dacomitinib) treatment (PMID: 32036069). 32036069
ERBB2 G778_P780dup lung adenocarcinoma predicted - sensitive Pyrotinib Case Reports/Case Series Actionable In a clinical study, three lung adenocarcinoma patients harboring ERBB2 (HER2) G778_P780dup (also reported as V777_G778insGSP) demonstrated a clinical benefit when treated with Pyrotinib, including a patient with three months of stable disease who had progressed on several prior lines of therapy, a patient with an ongoing partial response of six months, and a patient with an ongoing partial response of eight months who had prior disease progression with Gilotrif (afatinib) (PMID: 32036069). 32036069
ERBB2 G778_P780dup lung adenocarcinoma predicted - sensitive Afatinib + Cisplatin + Pemetrexed Disodium Case Reports/Case Series Actionable In a clinical case study, the combination of Gilotrif (afatinib), Platinol (cisplatin), and Alimta (Pemetrexed Disodium) followed by the combination of Gilotrif (afatinib) and Alimta (Pemetrexed Disodium) resulted in an ongoing partial response over 19 months in a patient with lung adenocarcinoma harboring ERBB2 (HER2) G778_P780dup (also reported as P780_Y781insGSP) (PMID: 32036069). 32036069
ERBB2 G778_P780dup lung adenocarcinoma predicted - sensitive Poziotinib Case Reports/Case Series Actionable In a clinical case study, Poziotinib (HM781-36B) treatment resulted in stable disease lasting nine months in a metastatic lung adenocarcinoma patient harboring ERBB2 (HER2) G778_P780dup (also reported as P780_Y781insGSP) with prior disease progression following an initial partial response to Gilotrif (afatinib) (PMID: 32036069). 32036069
ERBB2 G778_P780dup ERBB2 amp lung adenocarcinoma predicted - sensitive Pyrotinib Case Reports/Case Series Actionable In a clinical case study, Pyrotinib treatment resulted in 11 months of stable disease in a lung adenocarcinoma patient harboring ERBB2 (HER2) G778_P780dup (also reported as V777_G778insGSP) and ERBB2 (HER2) amplification (PMID: 32036069). 32036069
ERBB2 G778_P780dup lung adenocarcinoma predicted - sensitive Afatinib Case Reports/Case Series Actionable In a clinical study, five lung adenocarcinoma patients each harboring ERBB2 (HER2) G778_P780dup (also reported as P780_Y781insGSP) demonstrated a clinical benefit from treatment with Gilotrif (afatinib), including one patient with a partial response lasting nine months, a second patient demonstrating a 51% reduction in primary tumor size after one month with a partial response lasting eight months, and three patients with stable disease ranging from 6 to 9 months (PMID: 32036069). 32036069