Reference Detail

Ref Type Journal Article
PMID (26208524)
Authors Tang Z, Yuan X, Du R, Cheung SH, Zhang G, Wei J, Zhao Y, Feng Y, Peng H, Zhang Y, Du Y, Hu X, Gong W, Liu Y, Gao Y, Hao R, Li S, Wang S, Ji J, Zhang L, Sutton D, Wei M, Zhou C, Wang L, Luo L
Title BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers.
Journal Molecular cancer therapeutics
Vol 14
Issue 10
Date 2015 Oct
URL
Abstract Text Oncogenic BRAF, which drives cell transformation and proliferation, has been detected in approximately 50% of human malignant melanomas and 5% to 15% of colorectal cancers. Despite the remarkable clinical activities achieved by vemurafenib and dabrafenib in treating BRAF(V600E) metastatic melanoma, their clinical efficacy in BRAF(V600E) colorectal cancer is far less impressive. Prior studies suggested that feedback activation of EGFR and MAPK signaling upon BRAF inhibition might contribute to the relative unresponsiveness of colorectal cancer to the first-generation BRAF inhibitors. Here, we report characterization of a dual RAF kinase/EGFR inhibitor, BGB-283, which is currently under clinical investigation. In vitro, BGB-283 potently inhibits BRAF(V600E)-activated ERK phosphorylation and cell proliferation. It demonstrates selective cytotoxicity and preferentially inhibits proliferation of cancer cells harboring BRAF(V600E) and EGFR mutation/amplification. In BRAF(V600E) colorectal cancer cell lines, BGB-283 effectively inhibits the reactivation of EGFR and EGFR-mediated cell proliferation. In vivo, BGB-283 treatment leads to dose-dependent tumor growth inhibition accompanied by partial and complete tumor regressions in both cell line-derived and primary human colorectal tumor xenografts bearing BRAF(V600E) mutation. These findings support BGB-283 as a potent antitumor drug candidate with clinical potential for treating colorectal cancer harboring BRAF(V600E) mutation.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
BGB-283 BRAF Inhibitor 18 EGFR Inhibitor (Pan) 38 BGB-283 is a dual RAF kinase and EGFR inhibitor, which may lead to decreased tumor cell proliferation and reduced growth of tumors with activation of BRAF and/or EGFR (PMID: 26208524).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E Advanced Solid Tumor sensitive BGB-283 Preclinical - Cell culture Actionable In a preclinical study, BGB-283 inhibited viability of a variety of cancer cell lines harboring BRAF V600E in culture (PMID: 26208524). 26208524
BRAF V600E colorectal cancer sensitive BGB-283 + Cetuximab Preclinical - Cell line xenograft Actionable In a preclinical study, BGB-283 in combination with Erbitux (cetuximab) demonstrated enhanced tumor suppression in colorectal cancer cell line xenograft models harboring BRAF V600E (PMID: 26208524). 26208524
BRAF V600E colorectal cancer sensitive BGB-283 Preclinical - Pdx & cell culture Actionable In a preclinical study, BGB-283 inhibited Braf phosphorylation and cell proliferation in colorectal cancer cell lines harboring BRAF V600E in culture, and resulted in partial tumor regression in both cell line and patient-derived xenograft models (PMID: 26208524). 26208524
ERBB2 amp Her2-receptor positive breast cancer predicted - sensitive BGB-283 Preclinical - Cell culture Actionable In a preclinical study, BGB-283 inhibited proliferation of ERBB2 (HER2) amplified breast cancer cells in culture (PMID: 26208524). 26208524
BRAF V600E melanoma sensitive BGB-283 Phase I Actionable In a Phase I trial, BGB-283 resulted in partial response in 1 of 2 melanoma patients harboring BRAF V600E, who remained on treatment for over 249 days (AACR Annual Meeting, Apr 2016, abstract # CT005). detail...
BRAF V600E melanoma sensitive BGB-283 Preclinical - Cell culture Actionable In a preclinical study, BGB-283 inhibited Braf phosphorylation and cell proliferation in melanoma cell lines harboring BRAF V600E in culture (PMID: 26208524). 26208524
BRAF wild-type Advanced Solid Tumor resistant BGB-283 Preclinical - Cell culture Actionable In a preclinical study, a variety of BRAF wild-type tumor cell lines were insensitive to BGB-283 in culture (PMID: 26208524). 26208524