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|Ref Type||Journal Article|
|Authors||Liu S, Li S, Hai J, Wang X, Chen T, Quinn MM, Gao P, Zhang Y, Ji H, Cross DAE, Wong KK|
|Title||Targeting HER2 Aberrations in Non-Small Cell Lung Cancer with Osimertinib.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2018 Jun 01|
|Abstract Text||Purpose:HER2 (or ERBB2) aberrations, including both amplification and mutations, have been classified as oncogenic drivers that contribute to 2% to 6% of lung adenocarcinomas. HER2 amplification is also an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKI). However, due to limited preclinical studies and clinical trials, currently there is still no available standard of care for lung cancer patients with HER2 aberrations. To fulfill the clinical need for targeting HER2 in patients with non-small cell lung cancer (NSCLC), we performed a comprehensive preclinical study to evaluate the efficacy of a third-generation TKI, osimertinib (AZD9291).Experimental Design: Three genetically modified mouse models (GEMM) mimicking individual HER2 alterations in NSCLC were generated, and osimertinib was tested for its efficacy against these HER2 aberrations in vivoResults: Osimertinib treatment showed robust efficacy in HER2wt overexpression and EGFR del19/HER2 models, but not in HER2 exon 20 insertion tumors. Interestingly, we further identified that combined treatment with osimertinib and the BET inhibitor JQ1 significantly increased the response rate in HER2-mutant NSCLC, whereas JQ1 single treatment did not show efficacy.Conclusions: Overall, our data indicated robust antitumor efficacy of osimertinib against multiple HER2 aberrations in lung cancer, either as a single agent or in combination with JQ1. Our study provides a strong rationale for future clinical trials using osimertinib either alone or in combination with epigenetic drugs to target aberrant HER2 in patients with NSCLC. Clin Cancer Res; 24(11); 2594-604. ©2018 AACRSee related commentary by Cappuzzo and Landi, p. 2470.|
|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 wild-type||Advanced Solid Tumor||sensitive||Osimertinib||Preclinical||Actionable||In a preclinical study, Tagrisso (osimertinib) treatment resulted in antitumor efficacy in cells overexpressing wild-type ERBB2 (HER2), demonstrating inhibition of ERBB2 (HER2) phosphorylation and cell growth in culture and tumor regression in mouse models overexpressing wild-type ERBB2, with an 80% reduction in tumor volume (PMID: 29298799).||29298799|
|ERBB2 A775_G776insYVMA||Advanced Solid Tumor||sensitive||JQ1 + Osimertinib||Preclinical||Actionable||In a preclinical study, transgenic mouse models expressing ERBB2 (HER2) A775_G776insYVMA demonstrated greater tumor regression when treated with the combination of JQ1 and Tagrisso (osimertinib) compared to treatment with either agent alone, which resulted in little to no regression (PMID: 29298799).||29298799|