title: Overcoming dynamic molecular heterogeneity in metastatic colorectal cancer: Multikinase inhibition with regorafenib and the case of rechallenge with anti-EGFR.
abstract: In metastatic colorectal cancer (mCRC), fluorouracil-based combination therapy with oxaliplatin or irinotecan is the mainstay of first-line treatment. Patient survival has been significantly improved with the introduction of monoclonal antibodies against VEGF (bevacizumab), VEGFR2 (ramucirumab) or EGFR (cetuximab or panitumumab) in first- and second-line therapies. However, all patients treated with chemotherapy and targeted therapies will eventually relapse, and recently the emergence of alterations in EGFR, RAS, BRAF, ERB-B2, MET and possibly in other genes has been shown to jeopardize response to EGFR blockade. In chemorefractory patients, multikinase inhibition with regorafenib has proved to be effective and rechallenge with chemotherapy or anti-EGFR agents is empirically pursued. This review will critically discuss how the evolving knowledge of mechanisms of resistance driven by intratumoural dynamic molecular heterogeneity can impact on rational choice of treatments in this setting.
authors.affiliation: Department of Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda, 20162 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.affiliation: Department of Hematology and Oncology, Niguarda Cancer Center, Ospedale Niguarda, 20162 Milan, Italy; Department of Oncology, Università degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.affiliation: Department of Medical Oncology, Campus Bio-Medico University of Rome, 00128 Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tonini
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Torino, Italy; Department of Oncology, University of Torino, 10043 Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Department of Medical Oncology, Campus Bio-Medico University of Rome, 00128 Rome, Italy. Electronic address: d.santini@unicampus.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Clonal evolution; Drug resistance; EGFR; Metastatic colorectal cancer; Rechallenge therapy; Regorafenib