subject: The Role Of Raf265 In Raf Kinase. [print this page] Mutations in RAS gene are very common in different kinds of cancers and it has been very difficult to target this mutation as a part of therapy to different cancers. Alternative measures have been used while designing the inhibitors to the MAPK pathway. One such measure is to target the downstream kinases to RAS gene. Various preclinical studies have shown that tumors which show mutations in the RAS or BRAF are resistant to the inhibitors which act on the downstream kinases (RAK or MEK). The mutation within the RAF kinase at the 265th position and the mutation in the BRAF gene (replacement of val with glutamic acid at the 600th position) are involved in offering resistance to the inhibitors of RAF or MEK. Increased number of cells died when the action of protein kinase D3 was suppressed by knock down mechanism. This suggests that when PRKD3 is suppressed the action of MEK and RAK inhibitors was stimulated and this cooperates with RAF265. Ultimately it interrupts the progression of the cell cycle and stimulates the process of apoptosis. Blockade of PRKD3 along with the activation of RAF265 does not allow the formation of the colony of cancerous cells and their growth [2].
ACTIVITY OF RAF265 IS DRIVEN BY PI3K AND RAS-RAF PATHWAY
Certain chemotherapeutic agents and inhibitors of cancer fail to act on cancerous cells which show an overstimulation of KRAS and/or PI3K AKT as they offer resistance to EPGF inhibitors. The overstimulation of PI3K-AKT and/or KRAS pathway was inhibited by a novel inhibitor RAF265. This inhibitor worked well in combination with another inhibitor -RAD001 and they both showed significant antitumor activity under both in vitro and in vivo conditions. RAF265 was efficient in BRAF mutant cells and inhibited the kinase action of the substrates lying downstream to RAF. RAD001 suppresses the enzymes lying downstream to mTOR. A combination of these inhibitors reduces the levels phosphorylation of S6, AKT and eIF-4E binding protein 1 within HCT116 cell lines. The antitumoral action of RAF265 was further enhanced by RAD001. This suggests that when mTOR inhibitor is administered along with RAF265, the ras stimulated MAPK pathway and PI3K pathway are down-regulated [3].
CONCLUSION
To summarize RAF265 is an efficient inhibitor of RAF kinase and controls the growth of cancer, when administered in combination with other inhibitors. When the MAPK pathway is blocked by RAF265 (Raf inhibitor), it increased the sensitivity of the cells to TRAIL ligand. This stimulates the process of apoptosis within cancerous cells [4].
REFERENCES
1. Roberts PJ and Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancerTargeting the Raf-MEK-ERK MAPK cascade. Oncogene 2007 May 14; 26; 3291-3310.
2. Chen J, Shen Q, et al. Protein kinase D3 sensitizes RAF inhibitor RAF265 in melanoma cells by preventing reactivation of MAPK signaling. Cancer Res 2011 Apr 28.
3. Mordant P, Loriot Y, et al. Dependence on Phosphoinositide 3-Kinase and RAS-RAF Pathways Drive the Activity of RAF265, a Novel RAF/VEGFR2 Inhibitor, and RAD001 (Everolimus) in Combination. Mol Cancer Ther 2010 Feb; 9(2):358-68.
4. Zitzmann K, de Toni E, et al. The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells. Endocr Relat Cancer 2011 Mar 21; 18(2):277-85.
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