Emergence of Multiple EGFR Extracellular Mutations during Cetuximab Treatment in Colorectal Cancer

摘要: 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 treatment, molecular landscape resistant tumors must be ascertained. We investigated role mutations in EGFR signaling axis on acquisition patients and cellular models. Experimental Design: Tissue samples were obtained from 37 became refractory cetuximab. Colorectal cells sensitive treated until derivatives emerged. Mutational profiling biopsies cell was performed. Structural modeling functional analyses performed causally associate alleles resistance. Results: The genetic profile tumor specimens after treatment revealed emergence a complex pattern , KRAS NRAS BRAF PIK3CA genes, including two novel ectodomain (R451C K467T). cetuximab-resistant recapitulated observed clinical three additional alleles: S464L, G465R, I491M. Structurally, these are located cetuximab-binding region, except for R451C mutant. Functionally, prevent binding but subset is permissive interaction panitumumab. Conclusions: evade blockade by constitutive activation downstream effectors through affecting receptor–antibody binding. Both mechanisms may occur concomitantly. Our data have implications designing therapy relapse upon antibodies. Clin Cancer Res; 21(9); 2157–66. ©2015 AACR .