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B-RAF INHIBITOR AGAINST CANCERS

The mechanism of the RAS-Raf pathway

In the normal situation cells will live and die on a regular basis, maintaining healthy tissue and organs. To control this process there are several signaling pathway which either stimulate the cell to proliferate or induce the normal sequence of events for cell death (Apoptosis). The pathway which controls cell proliferation, cell differentiation and cell growth is the RAS/Raf/MEK/Erk pathway [1;2]Growth is initiated by the activation of RAS, which is located in the plasma membrane, by activation of its tyrosine kinase receptor by extracellular growth factors [3]. The RAS protein receptors are on the external face of the cell while signal is conducted inside the cell. Growth factors activate the external RAS protein so the internal root of the RAS protein complexes with Raf proteins activating them. The raf proteins then actively phosphorylates the MEK protein which in turn phosphorylates the Erl protein and cell division /proliferation beginnings [3;4]. The role of Raf is therefore to carry the signal from the activated RAS and to MEK protein in the cytosole/nuclease to initiate proliferation activity, the signal also acts as a cell survival mechanism. Therefore, in circumstances where the system is unhealthy the RAS-Raf pathway will ensure cell survival. Raf is therefore a critical protein in this process. Raf consists of 3 isoforms which initiate different survival mechanism (ARaf, BRaf and CRaf) [5;6]. Mutations in the encoding gene for these proteins can cause the BRaf protein to be activated and remain permanently activated without RAS triggering the event. This causes uncontrolled cellular reproduction and tissue growth. Mutations for BRaf have been discovered in a number of tumor types such as prostate, ovarian, colorectal, papillary and melanoma tumors to differing degrees. The mutation most commonly found in BRaf is the BRafV600E; it is associated with ~50% of all melanoma tumors [7], ~40% of papillary thyroid tumors[7], ~30% of advanced ovarian tumors[8;9] and ~10% of colorectal or prostate tumors [10;11].

Inhibition of BRaf

The rate of occurrence of the mutations in the BRaf protein found in such large proportions in a number of tumors make it an ideal target for chemotherapeutic action. B-Raf inhibition can be accomplished with small molecule inhibitors such as Darafenib, PLX-4720, Sorafenib, GFC-0879 and Vemurafenib [12]. Preclinical evidence demonstrated the effectiveness of this chemotherapeutic approach to the treatment of melanoma [13] which has translated into B-Raf inhibitor in clinical trials at phase I, phase II and phase III stages[14]. Vemurafenib has since been approved for use mestastic melanoma patients based the results of the phase III trials that ended in 2011 [15].

B-Raf selective inhibitors: Clinical Status

The B-Raf, cancer link has opened up the pathway for an effective treatment for some of the more difficult tumors. Research is on going for several tumor types with some success and some failures. In Melanoma cases, as has already been indicated, Vermufenib has been approved for use in the treatment of metastatic or unresectable melanoma [16]. However, not all BRaf inhibitors exhibit the same profile in melanoma patients since Sorafenib, a B-Raf kinase inhibitor, has been found to been ineffective against metastatic tumors [17;18]. With the use of B-Raf specific inhibitor PLX4729 it was observed that mutations other than just BRafv600E in the BRaf pathway dictate whether a clinical response would be seen, careful genotype screening was recommended for this type of patient. For colorectal cancer the KRAS & BRaf mutation is associated with clear clinical effects and patients with such mutations had a decreased overall survival compared to wild-type populations [19]. The use of BRaf inhibitors in this population group has not shown a demonstrable effect to date and KRAS mutation correlates more closely to disease status [20]. B-Raf antagonists in leukemia have been utilized against hairy cell leukemia where the BRafV600E mutation has been observed in all instances of this variety of cancer, however, limited response data is currently available. The same be said for thyroid and NSCL cancers [21-30], while the BRaf mutation has been identified in subset populations clinical response has yet to be determined. The B-Raf inhibitor drug is demonstrating clear benefits in certain genomic screened patient groups and research is ongoing. Researchers can buy B-Raf inhibitor from many commercial suppliers at reasonable cost.

References

 

   1.   Haluska F, Pemberton T et al. The RTK/RAS/BRAF/PI3K pathways in melanoma: biology, small molecule inhibitors, and potential applications. Semin Oncol 2007; 34(6):546-554.

   2.   Sundaram MV. RTK/Ras/MAPK signaling. WormBook 2006;1-19.

   3.   Maurer G, Tarkowski B et al. Raf kinases in cancer-roles and therapeutic opportunities. Oncogene 2011; 30(32):3477-3488.

   4.   Montagut C, Settleman J. Targeting the RAF-MEK-ERK pathway in cancer therapy. Cancer Lett 2009; 283(2):125-134.

   5.   McCubrey JA, Milella M et al. Targeting the Raf/MEK/ERK pathway with small-molecule inhibitors. Curr Opin Investig Drugs 2008; 9(6):614-630.

   6.   Aoki Y, Niihori T et al. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat 2008; 29(8):992-1006.

   7.   Malaponte G, Libra M et al. Detection of BRAF gene mutation in primary choroidal melanoma tissue. Cancer Biol Ther 2006; 5(2):225-227.

   8.   Mercer KE, Pritchard CA. Raf proteins and cancer: B-Raf is identified as a mutational target. Biochim Biophys Acta 2003; 1653(1):25-40.

   9.   Pritchard C, Carragher L et al. Mouse models for BRAF-induced cancers. Biochem Soc Trans 2007; 35(Pt 5):1329-1333.

10.   Cho NY, Choi M et al. BRAF and KRAS mutations in prostatic adenocarcinoma. Int J Cancer 2006; 119(8):1858-1862.

11.   Wickenden JA, Jin H et al. Colorectal cancer cells with the BRAF(V600E) mutation are addicted to the ERK1/2 pathway for growth factor-independent survival and repression of BIM. Oncogene 2008; 27(57):7150-7161.

12.   Zambon A, Niculescu-Duvaz I et al. Small molecule inhibitors of BRAF in clinical trials. Bioorg Med Chem Lett 2012; 22(2):789-792.

13.   Flaherty KT. BRAF Inhibitors and Melanoma. Cancer J 2011; 17(6):505-511.

14.   Zambon A, Niculescu-Duvaz I et al. Small molecule inhibitors of BRAF in clinical trials. Bioorg Med Chem Lett 2012; 22(2):789-792.

15.   Chapman PB, Hauschild A et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364(26):2507-2516.

16.   Heakal Y, Kester M et al. Vemurafenib (PLX4032): an orally available inhibitor of mutated BRAF for the treatment of metastatic melanoma. Ann Pharmacother 2011; 45(11):1399-1405.

17.   Davies MA, Fox PS et al. Phase I study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma. Clin Cancer Res 2012.

18.   Eisen T, Ahmad T et al. Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis. Br J Cancer 2006; 95(5):581-586.

19.   Kalady MF, Dejulius KL et al. BRAF Mutations in Colorectal Cancer Are Associated With Distinct Clinical Characteristics and Worse Prognosis. Dis Colon Rectum 2012; 55(2):128-133.

20.   Li HT, Lu YY et al. KRAS, BRAF and PIK3CA mutations in human colorectal cancer: relationship with metastatic colorectal cancer. Oncol Rep 2011; 25(6):1691-1697.

21.   Kobayashi M, Sonobe M et al. Clinical Significance of BRAF Gene Mutations in Patients with Non-small Cell Lung Cancer. Anticancer Res 2011; 31(12):4619-4623.

22.   Daud A, Bastian BC. Beyond BRAF in Melanoma. Curr Top Microbiol Immunol 2011.

23.   Ahn JB, Chung WB et al. DNA methylation predicts recurrence from resected stage III proximal colon cancer. Cancer 2011; 117(9):1847-1854.

24.   Ahn JB, Chung WB et al. DNA methylation predicts recurrence from resected stage III proximal colon cancer. Cancer 2010.

25.   Hemerly JP, Bastos AU et al. Identification of several novel non-p.R132 IDH1 variants in thyroid carcinomas. Eur J Endocrinol 2010; 163(5):747-755.

26.   Case M, Matheson E et al. Mutation of genes affecting the RAS pathway is common in childhood acute lymphoblastic leukemia. Cancer Res 2008; 68(16):6803-6809.

27.   Davidsson J, Lilljebjorn H et al. BRAF mutations are very rare in B- and T-cell pediatric acute lymphoblastic leukemias. Leukemia 2008; 22(8):1619-1621.

28.   Pedersen-Bjergaard J, Andersen MT et al. Genetic pathways in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia. Hematology Am Soc Hematol Educ Program 2007;392-397.

29.   Lee JW, Soung YH et al. BRAF mutations in acute leukemias. Leukemia 2004; 18(1):170-172.

30.   Bonello L, Voena C et al. BRAF gene is not mutated in plasma cell leukemia and multiple myeloma. Leukemia 2003; 17(11):2238-2240.

Related Products

Cat.No. Product Name Information
S1152 PLX-4720 PLX4720 is a potent and selective inhibitor of B-RafV600E with IC50 of 13 nM in a cell-free assay, equally potent to c-Raf-1(Y340D and Y341D mutations), 10-fold selectivity for B-RafV600E than wild-type B-Raf.

Related Targets

Raf