RESUMO
Introduction Triple negative breast cancer (TNBC) represents a heterogeneous subtype of breast cancer that carries a poorer prognosis. There remains a need to identify novel drivers of TNBC, which may represent targets to treat the disease. c-Met overexpression is linked with decreased survival and is associated with the basal subtype of breast cancer. Cpd A, a kinase inhibitor selective/specific for Met kinase has demonstrated preclinical anti-cancer efficacy in TNBC. We aimed to assess the anti-cancer efficacy of Cpd A when combined with Src kinase, ErbB-family or hepatocyte growth factor (HGF) inhibitors in TNBC cell lines. Methods We determined the anti-proliferative effects of Cpd A, rilotumumab, neratinib and saracatinib tested alone and in combination in a panel of TNBC cells by acid phosphatase assays. We performed reverse phase protein array analysis of c-Met and IGF1Rß expression and phosphorylation of c-Met (Y1234/1235) in TNBC cells and correlated their expression/phosphorylation with Cpd A sensitivity. We examined the impact of Cpd A, neratinib and saracatinib tested alone and in combination on invasive potential and colony formation.Results TNBC cells are not inherently sensitive to Cpd A, and neither c-Met expression nor phosphorylation are biomarkers of sensitivity to Cpd A. Cpd A enhanced the anti-proliferative effects of neratinib in vitro; however, this effect was limited to cell lines with innate sensitivity to Cpd A. Cpd A had limited anti-invasive effects but it reduced colony formation in the TNBC cell line panel.Conclusions Despite Cpd A having a potential role in reducing cancer cell metastasis, identification of strong predictive biomarkers of c-Met sensitivity would be essential to the development of a c-Met targeted treatment for an appropriately selected cohort of TNBC patients.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Fosfatase Ácida/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Proteínas Proto-Oncogênicas c-met/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
INTRODUCTION: The identification and validation of a targeted therapy for triple-negative breast cancer (TNBC) is currently one of the most urgent needs in breast cancer therapeutics. The cMET oncogene encodes a membrane-bound tyrosine kinase implicated in the formation and/or progression of several cancer types, including TNBC. Currently, inhibitors targeting cMET are undergoing clinical trials for a variety of cancers, including TNBC. These include anti-cMET and anti-hepatocyte growth factor (HGF) monoclonal antibodies and tyrosine kinase inhibitors. AREAS COVERED: This article reviews the structure and mode of action of cMET, the role of cMET in cancer formation/development, with particular emphasis on its role in basal/TNBC and its potential as a therapeutic target for this subtype of breast cancer. EXPERT OPINION: Due to cancer heterogeneity, it is unlikely that all TNBC patients will be responsive to anti-cMET drugs. Therefore, if cMET is to be used as a target for treatment, it will be important to identify predictive biomarkers to select, upfront, those patients likely to benefit. Potential predictive biomarkers for anti-cMET treatments in basal/TNBC include cMET, phospho-cMET, downstream signaling proteins or HGF. These putative predictive biomarkers should be evaluated in a large panel of basal/TNBC cell lines before incorporation into clinical trials involving anti-cMET drugs.