Combine MEK inhibition with PI3K/mTOR inhibition exert inhibitory tumor growth effect on KRAS and PIK3CA mutation CRC xenografts due to reduced expression of VEGF and matrix metallopeptidase-9

Abstract

Although epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) cetuximab are used widely to treat KRAS wild-type metastatic colorectal cancer (mCRC), patients become resistant by various mechanisms, including KRAS, BRAF, and PIK3CA mutations, thereafter relapsing. AZD6244 is a potent, selective, and orally available MEK1/2 inhibitor. In this study, we investigated the mechanisms of AZD6244 alone or with BEZ235, an orally available potent inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR), in a KRAS and PIK3CA mutation CRC xenograft model. HCT116 (KRAS (G13D) , PIK3CA (H1047R) mutant) cells were subcutaneously injected into the nude mice. Mice were randomly assigned to treatment with vehicle, cetuximab, AZD6244, BEZ235, or AZD6244 plus BEZ235, for up to 3 weeks; then, all mice were sacrificed, and tumor tissues were subjected to Western blot analysis and immunohistochemical staining. AZD6244 or BEZ235 slightly inhibit tumor growth of HCT116 xenografts, and the combination treatment markedly enhanced their antitumor effects. However, cetuximab had no effect on tumor growth. Western blot analysis and immunohistochemical staining revealed that treatment with AZD6244 or BEZ235 could significantly reduce the phosphorylation level of ERK1/2 or AKT in HCT116 tumor tissues. More interesting, the antiangiogenic effects were substantially enhanced when the agents were combined which may due to the reduced expression of VEGF and matrix metallopeptidase-9 (MMP-9) in tumor tissues. These results suggest that the combination of a selective MEK inhibitor and a PI3K/mTOR inhibitor was effective in CRC harboring with KRAS and PIK3CA mutations. The mechanisms of synergistic antitumor effects may be due to antiangiogenesis.

The selective MEK1 inhibitor Selumetinib enhances the antitumor activity of everolimus against renal cell carcinoma in vitro and in vivo

“…Interestingly, we found that the two drugs inhibit angiogenesis as a concomitant effect by suppressing VEGF secretion from tumor cells rather than a direct effect on vascular endothelial cells. Indeed combining MEK and mTOR inhibition exert antitumor effects on CRC xenografts due to reduced expression of VEGF [32]. Taken together, selumetinib enhances the antitumor activity of everolimus against RCC by synergistically inhibiting the expression of VEGF in addition to p-RPS6 and p-4E-BP1.…”

Pharmacogenomics of Targeted Agents for Personalization of Colorectal Cancer Treatment

“…Dactolisib (BEZ235), a PI3K/mTOR dual inhibitor, is another recently developed molecule that has raised interest since its synergism with the oral MEK1/2 inhibitor selumetinib. The combination of these two targeted agents has resulted in tumor growth blockade in KRAS - and PIK3CA -mutated CRC xenografts, and the antitumor effect seemed to be associated with a downregulation of matrix metallopeptidase-9 (MMP-9) and angiogenic blockade [ 74 ]. These pre-clinical results suggest that dual blockade of the PI3K and MEK pathways may overcome resistance to MEK inhibitors, providing the rationale for performing clinical trials of this combination in patients.…”

Dual Inhibition of MEK and PI3K Pathway in KRAS and BRAF Mutated Colorectal Cancers

“…Combination treatment demonstrated enhanced reduction in tumor growth against CRC cell line and patient-derived tumor xenograft models as compared to either single agent regardless of KRAS or PI3K mutational status. Recently, E et al [ 46 ] also reported their results on the use of BEZ235 with selumetinib in HCT116 CRC cells harboring both KRAS and PIk3CA mutations. The combination treatment markedly enhanced their antitumor effects than either single agent alone.…”

“…The combination treatment markedly enhanced their antitumor effects than either single agent alone. The authors also reported a reduction in the phosphorylation level of ERK1/2 and AKT and in the expression of VEGF and matrix metallopeptidase-9 in tumor tissue [ 46 ].…”