Abstract
With increasing clinical demands for MEK inhibitors in cancer treatment, overcoming the resistance to MEK inhibitors is an urgent problem to be solved. Numerous reports have shown that MEK inhibition results in the activation of PI3K-Akt signaling, which may confer apoptotic resistance to MEK inhibitors. We here demonstrate that the blockade of the mevalonate pathway using the antilipidemic drug statins represses Akt activation following MEK inhibition and induces significant apoptosis when co-treated with CH5126766 or trametinib. These events were clearly negated by the addition of mevalonate or geranylgeranyl pyrophosphate, indicating that the protein geranylgeranylation is implicated in the apoptotic resistance to MEK inhibitors. Furthermore, mechanistically, the combined treatment of CH5126766 with statins upregulated TNF-related apoptosis-inducing ligand (TRAIL), which was dependent on inhibition of the mevalonate pathway and is involved in apoptosis induction in human breast cancer MDA-MB-231 cells. The present study not only revealed that the mevalonate pathway could be targetable to enhance the efficacy of MEK inhibitors, but also proposes that combinatorial treatment of MEK inhibitors with statins may be a promising therapeutic strategy to sensitize cancer cells to apoptosis.
Highlights
MEK inhibitors are some of the most successful molecular-targeting drugs in recent years, as symbolized by the approval of trametinib against BRAF-mutated melanoma
The present study revealed that the mevalonate pathway could be targetable to enhance the efficacy of MEK inhibitors, and proposes that combinatorial treatment of MEK inhibitors with statins may be a promising therapeutic strategy to sensitize cancer cells to apoptosis
These results suggest that statins-mediated inhibition of the mevalonate pathway could increase the efficacy of MEK inhibitors
Summary
MEK inhibitors are some of the most successful molecular-targeting drugs in recent years, as symbolized by the approval of trametinib against BRAF-mutated melanoma. There has always been the underlying problem of resistance to MEK inhibitors. A number of mechanisms of MEK inhibitor resistance have been reported to date at both of genomic and nongenomic levels. The active mutation of PIK3CA gene or loss of function of PTEN gene led to the constitutive activation of PI3K-Akt signaling, which is known to confer resistance to MEK inhibition [4,5,6]. PIK3CA, Akt or PTEN genes are intact, MEK inhibition resulted in non-genomic Akt activation through feedback loops mediated by receptor tyrosine kinases, such as EGFR [7,8,9,10], FGFR [11, 12], IGF [13, 14], www.oncotarget.com
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