title: Acquired resistance to EGFR-targeted therapies in colorectal cancer.
abstract: Cetuximab and panitumumab are anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies used as therapies for metastatic colorectal cancer patients. Intrinsic mechanisms of resistance, such as RAS mutations, can prevent patients from having a response with clinical benefit. The clinical efficacy of EGFR targeted antibodies is limited by the development of acquired (secondary) resistance, which typically occurs within 3-12 months from the start of therapy. Preclinical models and analyses of clinical samples have uncovered some of the alterations that confer a selective advantage to tumor cells when under the pressure of anti-EGFR therapy. Molecular profiling of clinical specimens confirmed that genetic alterations of genes in the EGFR-RAS-RAF-MEK signaling pathway and of receptor tyrosine kinases are mechanisms of acquired resistance to anti-EGFR antibodies. The escape from anti-EGFR blockade appears to converge on the (re)activation of MEK-ERK or AKT as revealed in preclinical studies. Circulating tumor DNA and patient derived xenografts have proven useful tools to monitor patients for resistance to anti-EGFR therapy and test combination therapies to overcome or reverse resistance.
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy; FIRC Institute of Molecular Oncology (IFOM), Via Adamello, 16, 20139, Milan, Italy.
authors.forename: Beth O
authors.initials: BO
authors.lastname: Van Emburgh
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3, 20162, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy; University of Torino, Department of Oncology, Strada Provinciale, 142 km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3, 20162, Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy; University of Torino, Department of Oncology, Strada Provinciale, 142 km 3.95, 10060 Candiolo, Torino, Italy. Electronic address: alberto.bardelli@ircc.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D058990:Molecular Targeted Therapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012007:Rectum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins
keywords: Acquired resistance; Anti-EGFR therapy; Cetuximab; Colorectal cancer; MET; Panitumumab; RAS