With increasing clinical demands for MEK inhibitors in cancer treatment, overcoming the resistance to MEK inhibitors is becoming an important issue. Especially, the activation of PI3K-Akt pathway is well known to impede the sensitivity to MEK inhibitors. Indeed, a number of early-phase clinical studies, which test the combination efficacy of MEK and PI3K dual inhibition, have been performed; however, the results of these studies remain unsatisfactory. Thus, feasible combination therapies with MEK inhibitors are required to inhibit PI3K-Akt signaling. Mavalonate pathway is not only essential for cholesterol synthesis but also crucial for cell survival with prenylation of small GTPases, which are the upstreams of PI3K-Akt pathway. We thus hypothesized that the blockage of mevalonate pathway using the cholesterol-lowering drugs statins could enhance the efficacy of MEK inhibitors.
We used two MEK inhibitors: trametinib and CH5126766 (a dual RAF-MEK inhibitor under the phase 2 trials) and two mevalonate pathway blockers: fluvastatin and simvastatin against three cancer cell lines: human breast cancer MDA-MB-231, human melanoma SK-MEL28 and human non-small cell lung cancer A549. Cell growth was analyzed by WST-8 assays and colony formation assays. Apoptotic cells were quantified by flow cytometry. The activation of Akt and the expressions of apoptotic molecules were evaluated by western blotting.
The combined treatment of MEK inhibitors with statins induced significant increases of apoptosis in all cell lines compared to each single treatment. Mechanistically, single treatments of MEK inhibitors increased the phosphorylated Akt, which was suppressed by the addition of statins. Furthermore, the supplementation of mevalonate negated the combinatorial apoptosis.
The present study indicated that the inhibition of the mevalonate pathway suppressed the activation of Akt, resulting in the induction of MEK inhibitor-mediated apoptosis in cancer cells. We propose that statins can be feasible sensitizers for MEK inhibitors. While
Kyoto Prefectural University of Medicine
Has not received any funding
T. Taguchi: Research expenses from Eisai, Takeda, Daiichisankyo, Fuji film RI pharma, Chugai. All other authors have declared no conflicts of interest.