The MAPK pathway which is geared by Ras controls the expression of a large number of genes. In turn proteins involved in some of the vital processes within the cell like proliferation, apoptosis, cell division are all under the control of the MAPK pathway. The ERK is the ultimate effector of this pathway which regulates the phosphorylation of a number of cytoskeletal proteins and few transcription factors. A large number of inhibitors are being designed which can show potent action against the individual components of MAPK pathway. As hyper- activation of MAPK pathway has been found to be the cause behind many cancers. Amongst the various components of MAPK, activating mutations within the BRAF kinase have been found to be the leading cause behind thyroid cancers and melanomas. To be more precise BRAFV600E mutation leads to constitutive activation of MEK and ERK lying downstream in the MAPK pathway. This activation step does not require Ras-GTP. Inhibitors like PLX4032, RAF265 and sorafenib have been designed to inhibit the action of BRAF.
SPECIFIC CHARACTERS OF RAF265
The structure of RAF265 is derived from benz-azoles and it is a small molecule which shows potent action against RAF. It is highly selective in action and reduces the growth and proliferation of tumors. It acts as an angiogenesis inhibitor also as it has the capacity to bind to VEGFR-2. It shows potent action against all the three splice variants of RAF. However it inhibits the B-RafV600E mutant form more efficiently. It has proved its efficacy during the preclinical studies within the xenograft models. Very recently it has entered into phase I clinical testing against malignant melanomas [1].
THE DECREASE IN BCL-2 LEVELS STIMULATED BY RAF265
The TRAIL ligand plays a vital role in stimulating the process of apoptosis. Many tumors resist this pathway leading to apoptosis which moves via TRAIL. Due to this, they even try to resist the action of many chemotherapeutic agents which try to activate TRAIL within the cancerous cells. An aberrant PI3K signaling pathway leads to resistance to TRAIL. An imbalance between the proteins which stimulate and inhibit the process of apoptosis is generated. The sensitivity to TRAIL ligand is associated with the expression of proteins like caspase-8, Bcl-2 etc which in-turn stimulate the process of apoptosis. Upon administration of everolimus or NVP-BEZ235 (which inhibit mTOR), the sensitivity to TRAIL ligand was not instigated. On the other hand RAF265 successfully enhanced the sensitivity to the TRAIL ligand. This inhibitor acted only on Bcl2 protein by decreasing its levels. It did not show any effect on other pro-apoptotic proteins. These results suggest that administration of TRAIL along with RAF 265 can stimulate the process of apoptosis in many cases of cancers [2].
RAF 265 SENSITIZED BY PROTEIN KINASE D3
Mutations within the Ras or RAF kinase generally show a resistance to the inhibitors affecting the action of RAF and MEK1/2. When protein kinase D3 was knocked down in the RAF265 administered cells, the activity of inhibitors to RAF and MEK1/2 was enhanced within a large number of melanoma cells. These studies suggest that blockage of PRKD3 shows a synergistic action with Raf265 [3].
SYNERGISTIC ACTION OF RAF 265 WITH EVEROLIMUS
The combination of RAF265 and everolimus was tested on various cancer cell lines to asses the rate of cellular proliferation and cell viability. This combination was also tested within the xenograft models under in vivo conditions. Within HCT116 cells, this combination decreased the phosphorylated levels of S6, Akt and 4EBP1. This combination however showed no effect in MDAMB231 and A549 cells. These results suggest that this combination works well only in those cells which have a deregulated Ras-Raf and PI3K pathway [4].
CONCLUSION
In summary the selective inhibitor of BRAFV600E shows a potent action in many cases of cancers. It performs well in combination with other agents like TRAIL.
REFERENCES
1. Wong KK. Recent Developments in Anti-Cancer Agents Targeting the Ras/Raf/
MEK/ERK Pathway. Recent Patents on Anti-Cancer Drug Discovery 2009; 4: 28-35.
2. Zitzmann et al. The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells. Endocr Relat Cancer 2011 Apr 1; 18 : 277-285.
3. Chen et al. Protein Kinase D3 Sensitizes RAF Inhibitor RAF265 in Melanoma Cells by Preventing Reactivation of MAPK Signaling. Cancer Res 2011 June 15; 71: 4280.
4. 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;9: 358-368.
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