MET is a potential target for use in combination therapy with EGFR inhibition in triple‐negative/basal‐like breast cancer

MET, a cell surface receptor for hepatocyte growth factor, is involved in the development of triple‐negative/basal‐like breast cancer (TNBC/BLBC). However, its utility as a therapeutic target in this subtype of breast cancer is poorly understood. To evaluate MET fully as a potential therapeutic target for TNBC/BLBC, we investigated the relationship between MET expression and clinical outcomes of patients with breast cancer and the functional effect of MET inhibition. Using automated immunohistochemistry (Ventana), we analyzed MET expression in 924 breast cancer patients with relevant clinicopathologic parameters. BLBC showed the strongest relationship with MET expression (57.5%, p < 0.001). High expression of MET in breast cancer resulted in poor overall survival (p = 0.001) and disease‐free survival (DFS, p = 0.010). MET expression was relatively high in TNBC cell lines, and the silencing of MET via small interfering RNA reduced cell proliferation and migration. We observed reduced TNBC cell viability after treatment with the MET inhibitor PHA‐665752. In the most drug‐resistant cell line, MDA‐MB‐468, which showed elevated epidermal growth factor receptor (EGFR) expression, silencing of EGFR resulted in increased sensitivity to PHA‐665752 treatment. We confirmed that PHA‐665752 synergizes with the EGFR inhibitor erlotinib to decrease the viability of MDA‐MB‐468 cells. TNBC patients coexpressing MET and EGFR showed significantly worse DFS than that in patients expressing EGFR alone (p = 0.021). Our findings strongly suggest that MET may be a therapeutic target in TNBC and that the combined therapy targeting MET and EGFR may be beneficial for the treatment of TNBC/BLBC patients.

[1]  J. Engelman.  The Role of Phosphoinositide 3-Kinase Pathway Inhibitors in the Treatment of Lung Cancer , 2007, Clinical Cancer Research.

[2]  G. Wogan,et al.  The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[3]  L. Trusolino,et al.  Met signaling regulates growth, repopulating potential and basal cell-fate commitment of mammary luminal progenitors: implications for basal-like breast cancer , 2013, Oncogene.

[4]  T. Chou,et al.  Derivation and properties of Michaelis-Menten type and Hill type equations for reference ligands. , 1976, Journal of theoretical biology.

[5]  J. Lee,et al.  Triple-negative, basal-like, and quintuple-negative breast cancers: better prediction model for survival , 2010, BMC Cancer.

[6]  William Pao,et al.  MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib , 2007, Proceedings of the National Academy of Sciences.

[7]  P. Lollini,et al.  Retrogenic expression of the MET proto-oncogene correlates with the invasive phenotype of human rhabdomyosarcomas. , 1996, Oncogene.

[8]  G. Mills,et al.  cMET and Phospho-cMET Protein Levels in Breast Cancers and Survival Outcomes , 2012, Clinical Cancer Research.

[9]  M. Dimopoulos,et al.  High MET expression is an adverse prognostic factor in patients with triple-negative breast cancer , 2013, British Journal of Cancer.

[10]  R. Cardiff,et al.  Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer , 2009, Proceedings of the National Academy of Sciences.

[11]  M. Furihata,et al.  Overexpression of c-Met protein in human thyroid tumors correlated with lymph node metastasis and clinicopathologic stage. , 1999, Pathology, research and practice.

[12]  Karl J. Dykema,et al.  Met induces diverse mammary carcinomas in mice and is associated with human basal breast cancer , 2009, Proceedings of the National Academy of Sciences.

[13]  A. Gown,et al.  Immunohistochemical and Clinical Characterization of the Basal-Like Subtype of Invasive Breast Carcinoma , 2004, Clinical Cancer Research.

[14]  L. Schmidt,et al.  Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. , 1999, Cancer research.

[15]  F. Bertucci,et al.  Gene expression profiling of breast cell lines identifies potential new basal markers , 2006, Oncogene.

[16]  R. Motzer,et al.  Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. , 1994, Journal of the National Cancer Institute.

[17]  L. Schmidt,et al.  A novel germ line juxtamembrane Met mutation in human gastric cancer , 2000, Oncogene.

[18]  T. Chou,et al.  Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. , 1984, Advances in enzyme regulation.

[19]  S. Ethier,et al.  Met and c-Src cooperate to compensate for loss of epidermal growth factor receptor kinase activity in breast cancer cells. , 2008, Cancer research.

[20]  S. Ethier,et al.  EGFR/Met association regulates EGFR TKI resistance in breast cancer , 2010, Journal of molecular signaling.

[21]  L. Trusolino,et al.  The Met oncogene and basal-like breast cancer: another culprit to watch out for? , 2010, Breast Cancer Research.

[22]  S. Agarwal,et al.  Association of constitutively activated hepatocyte growth factor receptor (Met) with resistance to a dual EGFR/Her2 inhibitor in non-small-cell lung cancer cells , 2009, British Journal of Cancer.

[23]  L. Trusolino,et al.  MET signalling: principles and functions in development, organ regeneration and cancer , 2010, Nature Reviews Molecular Cell Biology.

[24]  E. Lengyel,et al.  C‐Met overexpression in node‐positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu , 2005, International journal of cancer.

[25]  K. Carraway,et al.  Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. , 2008, Cancer research.

[26]  G. V. Vande Woude,et al.  Autocrine hepatocyte growth factor/scatter factor-Met signaling induces transformation and the invasive/metastastic phenotype in C127 cells. , 1996, Oncogene.

[27]  Baljit Singh,et al.  Tissue microarray analysis of hepatocyte growth factor/Met pathway components reveals a role for Met, matriptase, and hepatocyte growth factor activator inhibitor 1 in the progression of node-negative breast cancer. , 2003, Cancer research.

[28]  L. Trusolino,et al.  Drug development of MET inhibitors: targeting oncogene addiction and expedience , 2008, Nature Reviews Drug Discovery.

[29]  B. Elliott,et al.  Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma. , 1996, The American journal of pathology.

[30]  Nakopoulou,et al.  c‐met tyrosine kinase receptor expression is associated with abnormal β‐catenin expression and favourable prognostic factors in invasive breast carcinoma , 2000, Histopathology.

[31]  D. Rimm,et al.  Tissue microarray‐based studies of patients with lymph node negative breast carcinoma show that met expression is associated with worse outcome but is not correlated with epidermal growth factor family receptors , 2003, Cancer.

[32]  David R. Croucher,et al.  Tyrosine phosphorylation profiling reveals the signaling network characteristics of Basal breast cancer cells. , 2010, Cancer research.

[33]  T. Nakamura,et al.  Creation of an hepatocyte growth factor/scatter factor autocrine loop in carcinoma cells induces invasive properties associated with increased tumorigenicity. , 1994, Oncogene.

[34]  Debra L Winkeljohn.  Triple-negative breast cancer. , 2008, Clinical journal of oncology nursing.

[35]  R. Tibshirani,et al.  Repeated observation of breast tumor subtypes in independent gene expression data sets , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  R. Gelber,et al.  Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011 , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[37]  Chris Albanese,et al.  ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. , 2012, The American journal of pathology.

[38]  G. V. Vande Woude,et al.  MET kinase inhibitor SGX523 synergizes with epidermal growth factor receptor inhibitor erlotinib in a hepatocyte growth factor-dependent fashion to suppress carcinoma growth. , 2010, Cancer research.

[39]  L. Pusztai,et al.  Use of standard markers and incorporation of molecular markers into breast cancer therapy , 2011, Cancer.

[40]  S. Serrano,et al.  FISH and immunohistochemical status of the hepatocyte growth factor receptor (c-Met) in 184 invasive breast tumors , 2009, Breast Cancer Research.

[41]  K. Yanagihara,et al.  Amplification of c-myc, K-sam, and c-met in gastric cancers: detection by fluorescence in situ hybridization. , 1998, Laboratory investigation; a journal of technical methods and pathology.

[42]  D. Beer,et al.  Genomic amplification of MET with boundaries within fragile site FRA7G and upregulation of MET pathways in esophageal adenocarcinoma , 2006, Oncogene.

[43]  Jie Qi,et al.  Multiple mutations and bypass mechanisms can contribute to development of acquired resistance to MET inhibitors. , 2011, Cancer research.

[44]  P Zola,et al.  Overexpression of the MET/HGF receptor in ovarian cancer , 1994, International journal of cancer.