Due to the lack of developing an effective Ras treatment, some have turned to targeting downstream effectors of Ras. Downstream effectors have a critical role in Ras carcinogenesis and are commonly found in KRAS mutated cancers. The most intensely targeted pathways are the Raf-MEK-ERK (MAPK) and PI3K-AKT-mTOR signaling pathways.
Raf-MEK-ERK
MAPK signaling is initiated through receptor tyrosine kinases after their activation by growth factors (Mccubrey 2006). Once Ras is in its active GTP bound state Ras is able to bind to many effectors, one of the most important being B-Raf. Active B-Raf phosphorylates and activates the kinases MEK 1/2, which in turn phosphorylates and activates ERK 1/2. The pathway regulates multiple important …show more content…
Vemurafenib is approved for the treatment of valine in exon 15, at codon 600 (V600E) mutant metastatic melanoma. It is a small molecule serine-threonine kinase inhibitor, which binds to the ATP-binding domain of mutant BRAF (Luke). These drugs are most effective in malignant melanomas, where NRAS and BRAF have been characterized to drive approximately 80% of lesions (Curtin). Vemurafenib proved effective in melanoma patients with B-Raf mutations with a response rate of greater than 50% and a rapid improvement in quality of life, it is not associated with complete remissions, but has a PFS of 6 to 7 months. Resistance mechanisms and combination therapies are currently being studied. Dabrafenib is similar to vemurafenib as they are both selective type I BRAF inhibitors that are effective in BRAFV600E metastatic melanoma. Some differences are that dabarefenib is more selective for BRAF than wild-type RAF, while vemurafenib has similar potency for CRAF, BRAF and BRAFV600E …show more content…
There are four main approaches to inhibition in the PI3K pathway, dual PI3K-mTOR inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. Since the p110 subunits of PI3K and mTOR have similar structures, the inhibition of p110 often results in the inhibition of mTOR (Garcia). This dual inhibition of PI3K-mTOR is expected to shut down PI3K-Akt-mTORC1 signaling, the issue surrounding this approach is whether patients will be able to tolerate the effects of the treatment. PI3K inhibitors can be isoform-specific or pan-PI3K inhibitors, which target all class I PI3Ks in the tumor. Advantages of an isoform specific treatment is a patient is more likely to tolerate a greater dose, but a concern is that the cancer will adapt to the treatment through a different PI3K isoform if a pan-PI3K inhibitor is not used (Engelman Targeting PI3K). AKT inhibitors are being targeted using ATP mimetics and non-catalytic site inhibitors (She breast cancer). Allosteric Akt inhibitors block the attachment of AKT to the membrane by interfering with the binding of the PH (Pleckstrin homology) domain to