A recent clinical trial in individuals with acute myelogen ous leukemia has shown that sufferers whose tumor cells have a higher ratio of expression of two genes, RASGRP1 and APTX, are extra most likely to respond to R115777. Therefore, in future trials it may well be of interest to de termine if this gene expression ratio can also be indicative in the dependence of melanoma tumors on farnesylation. For that reason, the choice of sufferers whose melanoma tumors express such a higher ratio may perhaps possess a higher likelihood of clinical responses. Understanding the mu tation status of RAS, BRAF and PI3K may perhaps also be in formative for predicting tumor sensitivity resistance and will be important for future function.
The mechanism of anti tumor activity of FTIs after they are helpful is incompletely understood, plus the majority of FTI trials have failed to demonstrate mean ingful clinical activity, regardless of confirmation that FTase or yet another intended target was inhibited. Multiple mechanisms of resistance and escape have been pro dig this posed. It can be doable, for example, that NRAS escapes the dependence on farnesylation and alternatively undergoes prenylation by geranylgeranyltransferase 1. Fur thermore, a much better understanding of the clinically rele vant FTI substrates is clearly necessary, enabling greater patient choice. A number of proteins undergo prenylation, and it can be most likely that a lot of are but to be identified. RAS loved ones proteins represent only a subset of molecules that undergo post translational modification by means of farnesy lation, and various option targets have already been proposed that may possibly be the most relevant for inhibition of tumor cell development.
Interestingly, using normal murine and human T cells as a model technique, we’ve observed that FTIs inhibited TCR dependent AG490 cytokine production beneath situations in which RAS pathway signaling was unaffected. Rather, in that program, inhibition of cytokine production appeared to take place at the post transcriptional level and was connected with inhibition of p70S6 Kinase activation. Rheb is often a candidate farnesylated protein that activates the p70S6 Kinase pathway. In vitro data suggest that the FTI lonafarnib may perhaps enhance the effects in the RAF inhibitor sorafenib by means of inhibition of mTOR signaling by blocking Rheb farnesylation. Subsequent studies have shown that inhibition of mTOR signaling with lonafarnib augments sorafenib induced apoptosis in melanoma cell lines.
Interestingly, this impact seemed to be independent of BRAF or NRAS mutation status. Hence, though these agents have been initially devel oped as RAS inhibitors, our collective information recommend that the effects of FTIs probably influence numerous signaling pathways. Of note, a randomized phase II trial comparing sorafe nib in mixture with either the mTOR inhibitor tem sirolimus or R115777 in an unselected patient population failed to demonstrate meaningful clinical activity.