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
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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