Antitumor Activity of BRAF Inhibitor Vemurafenib in Preclinical Models of BRAF-Mutant Colorectal Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 3; pp. 779 - 789
• Main Authors: HONG YANG, HIGGINS, Brian, LESTINI, Brian, BOLLAG, Gideon, FEI SU, KOLINSKY, Kenneth, PACKMAN, Kathryn, BRADLEY, William D, LEE, Richard J, SCHOSTACK, Kathleen, ELLEN SIMCOX, Mary, KOPETZ, Scott, HEIMBROOK, David
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.02.2012
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal, Humanized - administration & dosage; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Area Under Curve; Bevacizumab; Biological and medical sciences; Blotting, Western; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Capecitabine; Cell Line, Tumor; Cell Proliferation - drug effects; Cetuximab; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Erlotinib Hydrochloride; Fluorouracil - administration & dosage; Fluorouracil - analogs & derivatives; Gastroenterology. Liver. Pancreas. Abdomen; HCT116 Cells; HT29 Cells; Humans; Indoles - administration & dosage; Indoles - pharmacokinetics; Indoles - pharmacology; Kaplan-Meier Estimate; Medical sciences; Mice; Mice, Nude; Mitogen-Activated Protein Kinases - metabolism; Mutation; Pharmacology. Drug treatments; Phosphorylation - drug effects; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Quinazolines - administration & dosage; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Sulfonamides - administration & dosage; Sulfonamides - pharmacokinetics; Sulfonamides - pharmacology; Tumors; Xenograft Model Antitumor Assays; Antineoplastic agent; Rectal disease; Colorectal cancer; Preclinical trial; Malignant tumor; Biological activity; Colonic disease; Vemurafenib; BRAF Gene; C-Onc gene; Digestive diseases; Intestinal disease; Inhibitor; Models; Mutation; Protooncogene; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-11-2941

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.