Emergence of multiple EGFR extracellular mutations during cetuximab treatment in colorectal cancer

Sabrina Arena, Beatriz Bellosillo, Giulia Siravegna, Alejandro Martínez, Israel Cañadas, Luca Lazzari, Noelia Ferruz, Mariangela Russo, Sandra Misale, Iria González, Mar Iglesias, Elena Gavilan, Giorgio Corti, Sebastijan Hobor, Giovanni Crisafulli, Marta Salido, Juan Sánchez, Alba Dalmases, Joaquim Bellmunt, Gianni De FabritiisAna Rovira, Federica Di Nicolantonio, Joan Albanell, Alberto Bardelli, Clara Montagut

Research output: Contribution to journalArticlepeer-review


Purpose: Patients with colorectal cancer who respond to the anti-EGFR antibody cetuximab often develop resistance within several months of initiating therapy. To design new lines of treatment, the molecular landscape of resistant tumors must be ascertained. We investigated the role of mutations in the EGFR signaling axis on the acquisition of resistance to cetuximab in patients and cellular models. Experimental Design: Tissue samples were obtained from 37 patients with colorectal cancer who became refractory to cetuximab. Colorectal cancer cells sensitive to cetuximab were treated until resistant derivatives emerged. Mutational profiling of biopsies and cell lines was performed. Structural modeling and functional analyses were performed to causally associate the alleles to resistance. Results: The genetic profile of tumor specimens obtained after cetuximab treatment revealed the emergence of a complex pattern of mutations in EGFR, KRAS, NRAS, BRAF, and PIK3CA genes, including two novel EGFR ectodomain mutations (R451C and K467T). Mutational profiling of cetuximab-resistant cells recapitulated the molecular landscape observed in clinical samples and revealed three additional EGFR alleles: S464L, G465R, and I491M. Structurally, these mutations are located in the cetuximab- binding region, except for the R451C mutant. Functionally, EGFR ectodomain mutations prevent binding to cetuximab but a subset is permissive for interaction with panitumumab. Conclusions: Colorectal tumors evade EGFR blockade by constitutive activation of downstream signaling effectors and through mutations affecting receptor-antibody binding. Both mechanisms of resistance may occur concomitantly. Our data have implications for designing additional lines of therapy for patients with colorectal cancer who relapse upon treatment with anti-EGFR antibodies.

Original languageEnglish
Pages (from-to)2157-2166
Number of pages10
JournalClinical Cancer Research
Issue number9
Publication statusPublished - May 1 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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