Reference Detail

Ref Type Journal Article
PMID (23729478)
Authors Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, Sartore-Bianchi A, Scala E, Cassingena A, Zecchin D, Apicella M, Migliardi G, Galimi F, Lauricella C, Zanon C, Perera T, Veronese S, Corti G, Amatu A, Gambacorta M, Diaz LA, Sausen M, Velculescu VE, Comoglio P, Trusolino L, Di Nicolantonio F, Giordano S, Siena S
Title Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer.
Journal Cancer discovery
Vol 3
Issue 6
Date 2013 Jun
URL
Abstract Text 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.

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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
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
MET over exp colorectal cancer sensitive JNJ 38877605 + Panitumumab Preclinical - Cell culture Actionable In a preclinical study, the addition of JNJ-38877605 to Vectibix (panitumumab) treatment overcame Vectibix (panitumumab) resistance in colorectal cancer cell lines over expressing MET in culture (PMID: 23729478). 23729478
MET over exp colorectal cancer resistant Cetuximab Preclinical - Cell culture Actionable In a preclinical study, over expression of MET conferred resistance to Erbitux (cetuximab) in colorectal cancer cell lines in culture (PMID: 23729478). 23729478
MET over exp colorectal cancer sensitive Cetuximab + JNJ 38877605 Preclinical - Cell culture Actionable In a preclinical study, the addition of JNJ-38877605 to Erbitux (cetuximab) treatment overcame Erbitux (cetuximab) resistance in colorectal cancer cell lines over expressing MET in culture (PMID: 23729478). 23729478
MET amp colorectal cancer resistant Cetuximab Case Reports/Case Series Actionable In a clinical case study, MET amplification was associated with resistance to Erbitux (cetuximab) in 2 colorectal cancer patients, and in patient-derived xenograft (PDX) models (PMID: 23729478). 23729478
MET amp colorectal cancer sensitive JNJ 38877605 Preclinical - Pdx Actionable In a preclinical study, JNJ-38877605 inhibited tumor growth in colorectal cancer patient-derived xenograft models with MET amplification (PMID: 23729478). 23729478
MET over exp colorectal cancer resistant Panitumumab Preclinical - Cell culture Actionable In a preclinical study, over expression of MET conferred resistance to Vectibix (panitumumab) in colorectal cancer cell lines in culture (PMID: 23729478). 23729478