TY - JOUR
T1 - Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer
AU - Yang, Hong
AU - Higgins, Brian
AU - Kolinsky, Kenneth
AU - Packman, Kathryn
AU - Bradley, William D.
AU - Lee, Richard J.
AU - Schostack, Kathleen
AU - Simcox, Mary Ellen
AU - Kopetz, Scott
AU - Heimbrook, David
AU - Lestini, Brian
AU - Bollag, Gideon
AU - Su, Fei
PY - 2012/2/1
Y1 - 2012/2/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-11-2941
DO - 10.1158/0008-5472.CAN-11-2941
M3 - Article
C2 - 22180495
AN - SCOPUS:84863012433
SN - 0008-5472
VL - 72
SP - 779
EP - 789
JO - Cancer Research
JF - Cancer Research
IS - 3
ER -