Vemurafenib (PLX4032, RG7204) is a selective and potent inhibitor of B-RAF with IC50 values of 31 and 48nM for BRAFV600E and c-RAF-1, respectively [1]. Protein kinase B-RAF is a key component of the RAS-RAF signaling pathway, which plays a significant role in regulating cell proliferation, differentiation, and survival [2]. Vemurafenib can be used to induce autophagy and inhibit tumor growth [3-4].
In vitro, Vemurafenib (0.05-30μM; 2h) treatment significantly inhibited the phosphorylation of MEK and ERK in the melanoma cell lines Colo829 and LOX that express BRAFV600E. The inhibition of ERK and MEK phosphorylation by Vemurafenib is related to its inhibition of the growth of melanoma cells with V600 site mutations [5]. Vemurafenib (1μM; 24h) treatment significantly inhibited the growth, migration, and invasion of PC3 cells overexpressing Palm-PTK6-YF [6].
In vivo, Vemurafenib (12.5, 25, and 75mg/kg; 13d; p.o.) dose-dependently inhibited tumor growth in mice carrying LOX xenografts and induces tumor regression [5]. Vemurafenib (10mg/kg/day; 16d; i.p.) treatment had an inhibitory effect on tumor growth in C57BL/6 mice with subcutaneous inoculated SM1 tumors [7].
References:
[1] Bollag G, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature, 2010, 467(7315), 596-599.
[2] Yang H, Higgins B, Kolinsky K, et al. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer[J]. Cancer research, 2012, 72(3): 779-789.
[3] Wang W, et al. Targeting Autophagy Sensitizes BRAF-Mutant Thyroid Cancer to Vemurafenib.J Clin Endocrinol Metab. 2017 Feb 1;102(2):634-643.
[4] Lee W R, Shen S C, Shih Y H, et al. Early decline in serum phospho-CSE1L levels in vemurafenib/sunitinib-treated melanoma and sorafenib/lapatinib-treated colorectal tumor xenografts[J]. Journal of Translational Medicine, 2015, 13(1): 191.
[5] Yang H, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res, 2010, 70(13), 5518-5527.
[6] Wozniak D J, Hitchinson B, Gilic M B, et al. Vemurafenib inhibits active PTK6 in PTEN-null prostate tumor cells[J]. Molecular cancer therapeutics, 2019, 18(5): 937-946.
[7] Koya R C, Mok S, Otte N, et al. BRAF inhibitor vemurafenib improves the antitumor activity of adoptive cell immunotherapy[J]. Cancer research, 2012, 72(16): 3928-3937.
Vemurafenib (PLX4032, RG7204)是一种选择性的强效B-RAF抑制剂，对BRAFV600E和c-RAF-1的IC50分别为31和48nM[1]。蛋白激酶B-RAF是RAS-RAF信号通路的关键组成部分，该通路在调控细胞增殖、分化和存活方面发挥着重要作用 [2]。Vemurafenib可用于诱导细胞自噬和抑制肿瘤生长[3-4]。
在体外，Vemurafenib（0.05-30μM; 2h）处理显著抑制了表达BRAFV600E的黑色素瘤细胞系Colo829和LOX中MEK和ERK的磷酸化。Vemurafenib对ERK和MEK磷酸化的抑制与其对V600位点突变的黑色素瘤细胞细胞生长的抑制相关[5]。Vemurafenib（1μM; 24h）处理显著抑制了Palm-PTK6-YF过表达的PC3细胞的生长、迁移和侵袭 [6]。
在体内，Vemurafenib（12.5、25和75mg/kg; 13d; p.o.）剂量依赖性地抑制了携带LOX异种移植瘤的小鼠的肿瘤生长，并诱导肿瘤消退[5]。Vemurafenib（10mg/kg/day; 16d; i.p.）治疗对皮下接种SM1肿瘤的C57BL/6小鼠的肿瘤生长具有抑制作用 [7]。