Dataset Information

Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.

ABSTRACT: EGF receptor (EGFR)-targeted monoclonal antibodies are effective in a subset of metastatic colorectal cancers. Inevitably, all patients develop resistance, which occurs through emergence of KRAS mutations in approximately 50% of the cases. We show that amplification of the MET proto-oncogene is associated with acquired resistance in tumors that do not develop KRAS mutations during anti-EGFR therapy. Amplification of the MET locus was present in circulating tumor DNA before relapse was clinically evident. Functional studies show that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived colorectal cancer xenografts, MET amplification correlated with resistance to EGFR blockade, which could be overcome by MET kinase inhibitors. These results highlight the role of MET in mediating primary and secondary resistance to anti-EGFR therapies in colorectal cancer and encourage the use of MET inhibitors in patients displaying resistance as a result of MET amplification.

SUBMITTER: Bardelli A

PROVIDER: S-EPMC4078408 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Publications

Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.

Bardelli Alberto A Corso Simona S Bertotti Andrea A Hobor Sebastijan S Valtorta Emanuele E Siravegna Giulia G Sartore-Bianchi Andrea A Scala Elisa E Cassingena Andrea A Zecchin Davide D Apicella Maria M Migliardi Giorgia G Galimi Francesco F Lauricella Calogero C Zanon Carlo C Perera Timothy T Veronese Silvio S Corti Giorgio G Amatu Alessio A Gambacorta Marcello M Diaz Luis A LA Sausen Mark M Velculescu Victor E VE Comoglio Paolo P Trusolino Livio L Di Nicolantonio Federica F Giordano Silvia S Siena Salvatore S

Cancer discovery 20130602 6

EGF receptor (EGFR)-targeted monoclonal antibodies are effective in a subset of metastatic colorectal cancers. Inevitably, all patients develop resistance, which occurs through emergence of KRAS mutations in approximately 50% of the cases. We show that amplification of the MET proto-oncogene is associated with acquired resistance in tumors that do not develop KRAS mutations during anti-EGFR therapy. Amplification of the MET locus was present in circulating tumor DNA before relapse was clinically ...[more]

PMID: 23729478

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Project description:Epidermal growth factor receptor (EGFR), member of the human epidermal growth factor receptor (HER) family, plays a critical role in regulating multiple cellular processes including proliferation, differentiation, cell migration and cell survival. Deregulation of the EGFR signaling has been found to be associated with the development of a variety of human malignancies including lung, breast, and ovarian cancers, making inhibition of EGFR the most promising molecular targeted therapy developed in the past decade against cancer. Human non small cell lung cancers (NSCLC) with activating mutations in the EGFR gene frequently experience significant tumor regression when treated with EGFR tyrosine kinase inhibitors (TKIs), although acquired resistance invariably develops. Resistance to TKI treatments has been associated to secondary mutations in the EGFR gene or to activation of additional bypass signaling pathways including the ones mediated by receptor tyrosine kinases, Fas receptor and NF-kB. In more than 30-40% of cases, however, the mechanisms underpinning drug-resistance are still unknown. The establishment of cellular and mouse models can facilitate the unveiling of mechanisms leading to drug-resistance and the development or validation of novel therapeutic strategies aimed at overcoming resistance and enhancing outcomes in NSCLC patients. Here we describe the establishment and characterization of EGFR TKI-resistant NSCLC cell lines and a pilot study on the effects of a combined MET and EGFR inhibitors treatment. The characterization of the erlotinib-resistant cell lines confirmed the association of EGFR TKI resistance with loss of EGFR gene amplification and/or AXL overexpression and/or MET gene amplification and MET receptor activation. These cellular models can be instrumental to further investigate the signaling pathways associated to EGFR TKI-resistance. Finally the drugs combination pilot study shows that MET gene amplification and MET receptor activation are not sufficient to predict a positive response of NSCLC cells to a cocktail of MET and EGFR inhibitors and highlights the importance of identifying more reliable biomarkers to predict the efficacy of treatments in NSCLC patients resistant to EGFR TKI.

Dataset Information

Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.

Publications

Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.

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