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Oncogenic BRAF:
Turning off cancer signals

The RAS-RAF pathway, a type of MAPK signaling pathway, normally transmits signals, such as those from growth factors and hormones, to the nucleus, leading to the expression of genes that regulate cell proliferation and survival.1,2 Mutations in the proteins involved in the RAS-RAF pathway can lead to overactivation of the pathway and may contribute to oncogenic transformation.3,4

Cancer growth and hedgehog pathway
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The most common alteration in the BRAF gene is a mutation known as V600E.5 This mutation results in constitutively active BRAFV600E protein. As a result, overactivated downstream signaling via MEK and ERK leads to excessive cell proliferation and survival, independent of growth factors.1 BRAF mutations occur in ~50% of melanoma tumors, ~40% of papillary thyroid tumors, ~30% of serous ovarian tumors, ~10% of colorectal cancers, and ~10% of prostate tumors.4,6-11

Oncogenic BRAF signaling in this pathway may lead to1,2

  • Increased/uncontrolled cell proliferation
  • Resistance to apoptosis (programmed cell death)
  • Resistance to chemotherapy
References:
1.
McCubrey JA, Steelman LS, Chappell WH, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773:1263-1284.
2.
Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nature Rev Cancer. 2004;4:937-947.
3.
McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006;46:249-279.
4.
Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949-954.
5.
Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C. BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol Cancer Res. 2008;6:751-759.
6.
Cho NY, Choi M, Kim BH, Cho YM, Moon KC, Kang GH. BRAF and KRAS mutations in prostatic adenocarcinoma. Int J Cancer. 2006;119:1858-1862.
7.
Brose MS, Volpe P, Feldman M, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002;62:6997-7000.
8.
Fransén K, Klintenäs M, Osterström A, Dimberg J, Monstein HJ, Söderkvist P. Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis. 2004;25:527-533.
9.
Singer G, Oldt R 3rd, Cohen Y, et al. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst. 2003;95:484-486.
10.
Nikiforova MN, Kimura ET, Gandhi M, et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab. 2003;88:5399-5404.
11.
Wang L, Cunningham JM, Winters JL, et al. BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Res. 2003;63:5209-5212.
12.
Hoeflich KP, Herter S, Tien J, et al. Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res. 2009;69:3042-3051.