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|Ref Type||Journal Article|
|Authors||Leto SM, Sassi F, Catalano I, Torri V, Migliardi G, Zanella ER, Throsby M, Bertotti A, Trusolino L|
|Title||Sustained Inhibition of HER3 and EGFR Is Necessary to Induce Regression of HER2-Amplified Gastrointestinal Carcinomas.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2015 Dec 15|
|Abstract Text||Preclinical studies in HER2-amplified gastrointestinal cancer models have shown that cotargeting HER2 with a monoclonal antibody and a small molecule is superior to monotherapy with either inhibitor, but the underlying cooperative mechanisms remain unexplored. We investigated the molecular underpinnings of this synergy to identify key vulnerabilities susceptible to alternative therapeutic opportunities.The phosphorylation/activation of HER2, HER3, EGFR (HER receptors), and downstream transducers was evaluated in HER2-overexpressing colorectal and gastric cancer cell lines by Western blotting and/or multiplex phosphoproteomics. The in vivo outcome of antibody-mediated HER2 blockade by trastuzumab, reversible HER2 inhibition by lapatinib, and irreversible HER2 inhibition by afatinib was assessed in patient-derived tumorgrafts and cell-line xenografts by monitoring tumor growth curves and by using antibody-based proximity assays.Trastuzumab monotherapy reduced HER3 phosphorylation, with minor consequences on downstream transducers. Lapatinib alone acutely inhibited all HER receptors and effectors but led to delayed rephosphorylation of HER3 and EGFR and partial restoration of ERK and AKT activity. When combined with lapatinib, trastuzumab prevented HER3/EGFR reactivation and caused prolonged inhibition of ERK/AKT. Afatinib alone was also very effective in counteracting the reinstatement of HER3, EGFR, and downstream signaling activation. In vivo, the combination of trastuzumab and lapatinib-or, importantly, monotherapy with afatinib-resulted in overt tumor shrinkage.Only prolonged inhibition of HER3 and EGFR, achievable by dual blockade with trastuzumab and lapatinib or irreversible HER2 inhibition by single-agent afatinib, led to regression of HER2-amplified gastrointestinal carcinomas. Clin Cancer Res; 21(24); 5519-31. ©2015 AACR.|
|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 amp||colorectal cancer||decreased response||Lapatinib||Preclinical - Pdx||Actionable||In a preclinical study, treatment with Tykerb (lapatinib) resulted in initial disease stabilization with subsequent progression, in patient-derived colorectal cancer tumorgraft models with ERBB2 (HER2) amplification (PMID: 26296355).||26296355|
|ERBB2 amp||stomach cancer||sensitive||Lapatinib + Trastuzumab||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of Herceptin (trastuzumab) and Tykerb (lapatinib) treatment induced tumor regression in ERBB2 (HER2)-amplified cell line xenograft models of gastric cancer (PMID: 26296355).||26296355|
|ERBB2 amp||stomach cancer||sensitive||Trastuzumab||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Herceptin (trastuzumab) inhibited tumor growth in human cell line xenograft models of gastric cancer with ERBB2 (HER2) amplification (PMID: 26296355).||26296355|
|ERBB2 amp||colorectal cancer||resistant||Trastuzumab||Preclinical||Actionable||In a preclinical study, colorectal cancer tumorgrafts with ERBB2 (HER2) amplification demonstrated resistance to Herceptin (trastuzumab) treatment in animal models (PMID: 26296355).||26296355|
|ERBB2 over exp||colorectal cancer||resistant||Cetuximab||Preclinical - Cell line xenograft||Actionable||In a preclinical study, ERBB2 (HER2) over expression was associated with resistance to Erbitux (cetuximab) treatment in a human cell line xenograft model of colorectal cancer (PMID: 26296355).||26296355|
|ERBB2 amp||colorectal cancer||sensitive||Lapatinib + Trastuzumab||Preclinical - Pdx||Actionable||In a preclinical study, the combination of Herceptin (trastuzumab) and Tykerb (lapatinib) treatment induced tumor regression in patient-derived colorectal cancer tumorgraft models harboring ERBB2 (HER2) amplification (PMID: 26296355).||26296355|