title: Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution.
abstract: The EGFR-targeted antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancers. Mutations in KRAS, NRAS, and BRAF and amplification of ERBB2 and MET drive primary (de novo) resistance to anti-EGFR treatment. Recently, the emergence of alterations in the same genes was detected in patients who responded to EGFR blockade and then relapsed. These results illuminate a striking overlap between genes that, when mutated, drive primary and secondary resistance to anti-EGFR antibodies. Remarkably, although the mechanisms of resistance are genetically heterogeneous, they biochemically converge on key signaling pathways. This knowledge is being translated in the rational design of additional lines of therapy.
  
  
  CONCLUSIONS
  Anti-EGFR-targeted therapies are used for the treatment of metastatic colorectal cancer. Molecular heterogeneity impairs their efficacy by fuelling de novo and acquired resistance. In this review, we highlight how genetically distinct resistance mechanisms biochemically converge on a limited number of signaling pathways that can be therapeutically intercepted.
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy. Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Misale
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy. Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Department of Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.affiliation: Department of Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy. Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy. FIRC Institute of Molecular Oncology (IFOM), Milano, Italy. alberto.bardelli@unito.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D000077544:Panitumumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077544:Panitumumab; D066246:ErbB Receptors; D000068818:Cetuximab