title: Molecular Pathways: Sensitivity and Resistance to Anti-EGFR Antibodies.
abstract: Monoclonal antibodies targeting the EGF receptor (EGFR) tyrosine kinase, such as cetuximab and panitumumab, achieve clinically meaningful responses in patients affected by head and neck and colorectal cancers. Despite this evidence of efficacy, no genomic abnormalities that robustly predict sensitivity to EGFR blockade have been yet identified. This suggests that, in some tumor contexts, EGFR dependency is not acquired during neoplastic transformation and rather reflects an aberrant declination of physiologic traits typical of normal tissue counterparts. Indeed, EGFR signals are crucial for the reconstitution of damaged mucosa in the context of acute inflammation, and their sustained activation is likely to turn into a pro-oncogenic cue during chronic inflammation. Although positive predictors of response to anti-EGFR antibodies remain unknown, multiple determinants of resistance have been described, including alterations interfering with antibody-receptor interaction, deregulation of parallel signaling pathways, and mutations in downstream transducers. These findings provide new opportunities for the optimization of therapeutic strategies based on drug combinations. However, the emerging notion that genetic interactions and compensatory mechanisms may affect-both positively and negatively-the efficacy of targeted therapies complicates the rational design of combinatorial approaches and implies a rethinking of the criteria required to prioritize laboratory findings for clinical validation in investigational trials.
authors.affiliation: Department of Oncology, University of Torino Medical School, Candiolo (Torino), Italy. Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute-FPO IRCCS, Candiolo (Torino), Italy. Istituto Nazionale di Biostrutture e Biosistemi, INBB, Rome, Italy. andrea.bertotti@unito.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
authors.affiliation: Laboratory of Translational Cancer Medicine, Candiolo Cancer Institute-FPO IRCCS, Candiolo (Torino), Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sassi
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D058990:Molecular Targeted Therapy; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; C512478:EGFR protein, human; D066246:ErbB Receptors