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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	14	10	2015 Oct	2187-97	Mol Cancer Ther

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	Drugs	Efficacy Evidence	Clinical Trials
Lifirafenib	Lifirafenib	12	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Lifirafenib		BGB-283	BRAF Inhibitor 25 EGFR Inhibitor (Pan) 62	Lifirafenib (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, PMID: 32182156).

Gene	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	Lifirafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Lifirafenib (BGB-283) inhibited viability of a variety of cancer cell lines harboring BRAF V600E in culture (PMID: 26208524).	26208524
BRAF V600E	colorectal cancer	sensitive	Lifirafenib	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, Lifirafenib (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
BRAF V600E	colorectal cancer	sensitive	Cetuximab + Lifirafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Lifirafenib (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	melanoma	sensitive	Lifirafenib	Preclinical - Cell culture	Actionable	In a preclinical study, Lifirafenib (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	no benefit	Lifirafenib	Preclinical - Cell culture	Actionable	In a preclinical study, a variety of BRAF wild-type tumor cell lines were insensitive to Lifirafenib (BGB-283) in culture (PMID: 26208524).	26208524