Emergence of Multiple EGFR Extracellular Mutations during Cetuximab Treatment in Colorectal Cancer
Autor: | Noelia Ferruz, Israel Cañadas, Alba Dalmases, Joaquim Bellmunt, Marta Salido, Federica Di Nicolantonio, Giorgio Corti, Alberto Bardelli, Mar Iglesias, Juan Sánchez, Giovanni Crisafulli, Elena Gavilán, Sandra Misale, Alejandro Martínez, Joan Albanell, Clara Montagut, Iria Gonzalez, Gianni De Fabritiis, Beatriz Bellosillo, Mariangela Russo, Giulia Siravegna, Sabrina Arena, Ana Rovira, Sebastijan Hobor, Luca Lazzari |
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Rok vydání: | 2015 |
Předmět: |
Neuroblastoma RAS viral oncogene homolog
Oncology Cancer Research medicine.medical_specialty Colorectal cancer Blotting Western DNA Mutational Analysis Antineoplastic Agents colorectal cancer oncogenic mutations Drug resistance Real-Time Polymerase Chain Reaction medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Internal medicine Anti-EGFR antibodies cetuximab medicine Humans Panitumumab neoplasms 030304 developmental biology 0303 health sciences biology Cetuximab business.industry Genes erbB-1 Flow Cytometry medicine.disease Epidermal Growth Factor Receptor (EGFR) digestive system diseases 3. Good health Ectodomain Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mutation biology.protein KRAS EGFR mutation Antibody Colorectal Neoplasms Extracellular Space panitumumab business medicine.drug |
Zdroj: | Clinical Cancer Research. 21:2157-2166 |
ISSN: | 1557-3265 1078-0432 |
Popis: | 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. Clin Cancer Res; 21(9); 2157–66. ©2015 AACR. |
Databáze: | OpenAIRE |
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