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.
©2011 AACR.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal, Humanized / administration & dosage
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Area Under Curve
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Bevacizumab
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Blotting, Western
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Camptothecin / administration & dosage
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Camptothecin / analogs & derivatives
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Capecitabine
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cetuximab
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / pathology
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Deoxycytidine / administration & dosage
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Deoxycytidine / analogs & derivatives
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / drug effects
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Erlotinib Hydrochloride
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Fluorouracil / administration & dosage
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Fluorouracil / analogs & derivatives
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HCT116 Cells
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HT29 Cells
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Humans
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Indoles / administration & dosage
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Indoles / pharmacokinetics
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Indoles / pharmacology*
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Irinotecan
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Kaplan-Meier Estimate
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Mice
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Mice, Nude
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Mitogen-Activated Protein Kinases / metabolism
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Mutation
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Phosphorylation / drug effects
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism
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Quinazolines / administration & dosage
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Sulfonamides / administration & dosage
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology*
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Vemurafenib
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Xenograft Model Antitumor Assays*
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Indoles
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Quinazolines
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Sulfonamides
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Deoxycytidine
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Vemurafenib
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Bevacizumab
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Capecitabine
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Irinotecan
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Erlotinib Hydrochloride
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Mitogen-Activated Protein Kinases
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Cetuximab
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Fluorouracil
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Camptothecin