American Association for Cancer Research
21598290cd120558-sup-fig_s5.pdf (777.33 kB)

Supplementary Figure S5 from Amplification of the MET Receptor Drives Resistance to Anti-EGFR Therapies in Colorectal Cancer

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journal contribution
posted on 2023-04-03, 20:27 authored by Alberto Bardelli, Simona Corso, Andrea Bertotti, Sebastijan Hobor, Emanuele Valtorta, Giulia Siravegna, Andrea Sartore-Bianchi, Elisa Scala, Andrea Cassingena, Davide Zecchin, Maria Apicella, Giorgia Migliardi, Francesco Galimi, Calogero Lauricella, Carlo Zanon, Timothy Perera, Silvio Veronese, Giorgio Corti, Alessio Amatu, Marcello Gambacorta, Luis A. Diaz, Mark Sausen, Victor E. Velculescu, Paolo Comoglio, Livio Trusolino, Federica Di Nicolantonio, Silvia Giordano, Salvatore Siena

Supplementary Figure S5 - PDF file 777K, Schematic representation of the scoring system applied to assess MET protein expression by immunohistochemistry



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.Significance: Amplification of the MET proto-oncogene is responsible for de novo and acquired resistance to anti-EGFR therapy in a subset of colorectal cancers. As multiple anti-MET therapeutic strategies are available, these findings offer immediate novel opportunities to design clinical studies. Cancer Discov; 3(6); 658–73. ©2013 AACR.This article is highlighted in the In This Issue feature, p. 591