The mechanisms regulating the inhibitory effects of lovastatin on EGFR function and the synergistic cytotoxicity in combination with gefitinib are currently not known. These findings suggest that mevalonate pathway inhibitors and receptor TKI may represent a novel combinational therapeutic approach in a variety of human cancers. The VEGFR and the EGFR are both members of RTK family that share similar activation, internalization and downstream signaling characteristics. Cycloheximide Therefore, PCI-32765 targeting the mevalonate pathway may have similar inhibitory effects on VEGFR and may also enhance the activity of VEGFR-TKI. VEGFR, particularly VEGFR-2, play important roles in regulating angiogenesis by promoting endothelial cell proliferation, survival and migration. VEGF and VEGFR are also expressed by some tumor cells, like MM, acting in a functional autocrine loop capable of directly stimulating the growth and survival of MM cells. In this study, we have shown lovastatin does indeed inhibit ligand-induced VEGFR-2 activation through inhibition of receptor internalization resulting in diminished AKT activation in HUVEC and MM cells. Lovastatin treatment re-organized the actin cytoskeleton, inhibited proliferation and induced apoptosis of HUVEC at therapeutically relevant doses despite addition of exogenous VEGF. AKT activation, which mediates cell survival, along with its downstream targets S6K1 and 4EBP1 were significantly inhibited by lovastatin treatment. Combining lovastatin with VEGFR-TKIs also induced synergistic cytotoxicity of HUVEC cells. Due to their role in promoting tumor neovascularization, inhibiting the function of VEGF and VEGFR has been the focus of a number of therapeutic approaches. The limited clinical responses associated with these agents have been associated with their ability to promote disease stabilization and rarely induce tumor regression. Thus, agents that can cooperate and enhance the activity of VEGFR-TKI, like lovastatin, may increase their therapeutic activity. MM is a highly aggressive tumor that is rarely curative and median survival is in the range of 10�C17 months, therefore, novel therapies for MM are needed. Elevated levels of circulating and serousal VEGF in MM patients and the expression of VEGF and VEGFR on MM cells that can drive their proliferation and enhance their survival has led to the evaluation of VEGFR targeted therapies. Bevacizumab, a monoclonal antibody against the VEGF, which is approved for the treatment of colon cancer, in combination with chemotherapy, failed to significantly affect outcome to chemotherapy treatment alone. Various VEGFRTKI employed a single agents also failed to demonstrate clinical utility in MM patients. As like HUVEC, MM cells also depend on VEGFR signaling, we also examined the effect of lovastatin alone and in combination with VEGFR-2 TKI on MM cell viability. Combining 5 mM lovastatin treatments with two VEGFR-2 inhibitors in the H28 and H2052 mesothelioma derived cell lines demonstrated synergistic cytotoxicity through the induction of a potent apoptotic response. These results highlight a novel mechanism regulating VEGFR-2 function and a potential novel therapeutic approach for MM. Inhibition of HMG-CoA reductase has been evaluated as an anti-cancer therapeutic approach owing to its ability to inhibit tumor cell proliferation, induce tumor specific apoptosis and inhibit cell motility and metastasis in several tumor models. A number of Phase I Clinical trials evaluating the efficacy of high doses of lovastatin failed to demonstrate significant antitumor activity.