title: Dual targeting of HER3 and EGFR in colorectal tumors might overcome anti-EGFR resistance.
abstract: Multiple genetic alterations have been associated with resistance to anti-EGFR therapy in metastatic colorectal cancer (CRC) patients. Research has been mainly focused on driver mutations in KRAS, NRAS, BRAF and PI3K. However, recent evidence suggests a crucial role for non-genetic mechanisms in conferring resistance to anti-EGFR therapy. Specifically, the HER3 receptor is capable of heterodimerizing with multiple EGFR family members resulting in downstream activation of the PI3K and MAPK pathways. Monoclonal antibodies targeted against the HER3 receptor are being investigated in clinical trials; however, preliminary data has shown limited clinical activity. Thus, given the relevance of the HER3 receptor in activating downstream effector pathways and in conferring resistance to anti-EGFR therapy, the therapeutic targeting of HER3 in combination with primary drivers of the tumor is also being investigated. Here, we review the role of HER3 as a promoter of clinical resistance to EGFR therapy and discuss therapeutic approaches that could potentially overcome this resistance.
authors.affiliation: Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, 110 72020 Beirut, Lebanon. Electronic address: st29@aub.edu.lb.
authors.forename: Sally
authors.initials: S
authors.lastname: Temraz
authors.affiliation: Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, 110 72020 Beirut, Lebanon.
authors.forename: Deborah
authors.initials: D
authors.lastname: Mukherji
authors.affiliation: Department of Internal Medicine, Hematology/Oncology Division, American University of Beirut Medical Center, Riad El Solh, 110 72020 Beirut, Lebanon.
authors.forename: Ali
authors.initials: A
authors.lastname: Shamseddine
mesh_terms: D000906:Antibodies / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000906:Antibodies; C512478:EGFR protein, human; C581292:ERBB3 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3
keywords: Colorectal cancer; Drug resistance; EGFR; HER3; Monoclonal antibodies