The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition

Abstract

Background:Combined targeting of MAPK and PI3K signalling pathways may be necessary for optimal therapeutic activity in cancer. This study evaluated the MEK inhibitors AZD6244 and PD0325901, alone and in combination with the dual mTOR/PI3K inhibitor NVP-BEZ235 or the PI3K inhibitor GDC-0941, in three colorectal cancer cell lines.Methods:Growth inhibition, survival and signal transduction were measured using the Sulforhodamine B assay, clonogenicity and western blotting, respectively, in HCT116, HT29 and DLD1 cell lines.Results:All MEK/PI3K inhibitor combinations exhibited marked synergistic growth inhibition; however, GDC-0941 displayed greater synergy in combination with either MEK inhibitor. NVP-BEZ235 exhibited stronger inhibition of 4EBP1 phosphorylation, and similar inhibition of S6 and AKT phosphorylation, compared with GDC-0941. Both PD0325901 and AZD6244 inhibited ERK phosphorylation, and with MEK/PI3K inhibitor combinations inhibition of S6 phosphorylation was increased. The reduced synergy exhibited by NVP-BEZ235 in combination with MEK inhibitors, compared with GDC-0941, may be due to inhibition of mTOR, and the addition of the mTORC1/2 inhibitor KU0063794 compromised the synergy of GDC-0941:PD0325901 combinations.Conclusion:These studies confirm that dual targeting of PI3K and MEK can induce synergistic growth inhibition; however, the combination of specific PI3K inhibitors, rather than dual mTOR/PI3K inhibitors, with MEK inhibitors results in greater synergy.

PI3K Inhibitors Synergize with FGFR Inhibitors to Enhance Antitumor Responses in FGFR2mutant Endometrial Cancers

“…Together with previous studies targeting the PI3K pathway alone or in combination with MEK inhibition, these results indicate that levels of phosphorylated S6 may be an effective biomarker of response to targeting these key survival pathways (32)(33)(34).…”

The comparison between dual inhibition of mTOR with MAPK and PI3K signaling pathways in KRAS mutant NSCLC cell lines

“…As shown in our study, dual inhibition of mTOR and ERK-MAPK or PI3K-AKT pathways may overcome the disadvantage of single-agent therapies and enhance the efficacy of mTOR-targeted therapies. Also, targeting PI3K, MEK, and mTOR all together is more effective than dual inhibitors [49]. However, considering the side effects, it would be difficult to treat patients with all these inhibitors at the same time.…”

Colorectal Cancers

“…This observation has led to the hypothesis that more efficient mTOR inhibition and anticancer effects in CRC could also be achieved via combined use of inhibitors of both pathways. In support of this notion, synergistic effects were observed in CRC cell lines using combinations of MEK (AZD6244 and PD032590) and PI3K inhibitors (GDC-0941) or dual mTOR/PI3K NVP-BEZ235 (Haagensen et al 2012). Such a combination with the MEK inhibitor MSC1936369B and the PI3K inhibitor SAR245409 is entering clinical testing in locally advanced or metastatic solid tumors (including CRC) (see clinicaltrials.gov NCT01390818).…”