title: Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer.
abstract: The protein kinase BRAF is a key component of the RAS-RAF signaling pathway which plays an important role in regulating cell proliferation, differentiation, and survival. Mutations in BRAF at codon 600 promote catalytic activity and are associated with 8% of all human (solid) tumors, including 8% to 10% of colorectal cancers (CRC). Here, we report the preclinical characterization of vemurafenib (RG7204; PLX4032; RO5185426), a first-in-class, specific small molecule inhibitor of BRAF(V600E) in BRAF-mutated CRC cell lines and tumor xenograft models. As a single agent, vemurafenib shows dose-dependent inhibition of ERK and MEK phosphorylation, thereby arresting cell proliferation in BRAF(V600)-expressing cell lines and inhibiting tumor growth in BRAF(V600E) bearing xenograft models. Because vemurafenib has shown limited single-agent clinical activity in BRAF(V600E)-mutant metastatic CRC, we therefore explored a range of combination therapies, with both standard agents and targeted inhibitors in preclinical xenograft models. In a BRAF-mutant CRC xenograft model with de novo resistance to vemurafenib (RKO), tumor growth inhibition by vemurafenib was enhanced by combining with an AKT inhibitor (MK-2206). The addition of vemurafenib to capecitabine and/or bevacizumab, cetuximab and/or irinotecan, or erlotinib resulted in increased antitumor activity and improved survival in xenograft models. Together, our findings suggest that the administration of vemurafenib in combination with standard-of-care or novel targeted therapies may lead to enhanced and sustained clinical antitumor efficacy in CRCs harboring the BRAF(V600E) mutation.
authors.affiliation: Roche Pharmaceuticals, Nutley, New Jersey 07110, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kolinsky
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
authors.forename: William D
authors.initials: WD
authors.lastname: Bradley
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Kathleen
authors.initials: K
authors.lastname: Schostack
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Simcox
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.forename: David
authors.initials: D
authors.lastname: Heimbrook
authors.forename: Brian
authors.initials: B
authors.lastname: Lestini
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
authors.forename: Fei
authors.initials: F
authors.lastname: Su
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D000068258:Bevacizumab; D015153:Blotting, Western; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069287:Capecitabine; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000069347:Erlotinib Hydrochloride; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007211:Indoles; D011799:Quinazolines; D013449:Sulfonamides; D003841:Deoxycytidine; D000077484:Vemurafenib; D000068258:Bevacizumab; D000069287:Capecitabine; D000077146:Irinotecan; D000069347:Erlotinib Hydrochloride; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D000068818:Cetuximab; D005472:Fluorouracil; D002166:Camptothecin