Antitumor activity of a combination of dual PI3K/mTOR inhibitor SAR245409 and selective MEK1/2 inhibitor pimasertib in endometrial carcinomas

Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging

“…SAR245409 and pimasertib were provided by Sanofi (Paris, France) and Merck Serono (Darmstadt, Germany), respectively. SAR245409 is a highly selective and potent ATP-competitive inhibitor of pan-class I PI3Ks and mTORC1/mTORC2 [ 17 , 39 ]. Pimasertib is a highly potent ATP-noncompetitive second-generation inhibitor of MEK1 and MEK2.…”

“…Cell proliferation was evaluated in MTT assays using the Cell Counting Kit-8 (Dojindo, Tokyo, Japan) or Cell Count Reagents SF (Nacalai Tesque, Kyoto, Japan), both of which employ 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl) -2H-tetrazolium, monosodium salt [ 17 , 41 ]. Cells were seeded in 96-well plates at 2 × 10 3 −1 × 10 4 cells/well and exposed to each drug for 72 h. Cell proliferation was quantified by monitoring changes in the absorbance at 450 nm.…”

“…Cells (5 × 10 5 ) in 6-well plates were exposed to SAR245409 and/or pimasertib for the indicated times at the indicated concentrations and lysed as described previously [ 43 ]. Primary antibodies against AKT, p-AKT (Ser473), S6K, phosphorylated S6K (p-S6K), ERK, p-ERK (ERK1/2-Thr202/Tyr204) (Cell Signaling Technology, Beverly, MA, USA), and beta-actin (Sigma-Aldrich, St. Louis, MO, USA) were used for immunoblotting [ 17 , 23 ]. Signals were detected using an immunoblotting system (BioRad Laboratories, Hercules, CA, USA) with ECL Select Detection agents (GE Healthcare, Piscataway, NJ, USA).…”

“…However, the antitumor effects of these drugs vary significantly among cancer types [ 14 ], which might relate to the complexity of the signaling networks [ 15 , 16 ]. We recently reported that combination treatment with a PI3K/mTOR inhibitor, SAR245409 (voxtalisib), and a MEK inhibitor, pimasertib, showed synergistic antitumor effects in 6 out of 12 endometrial cancer cell lines and that mutational statuses of KRAS , PIK3CA , and PTEN were not involved [ 17 ]. Pimasertib, alone or in combination with SAR245409, is currently being investigated in Phase I–II trials.…”

Characterization of TP53 and PI3K signaling pathways as molecular targets in gynecologic malignancies

“…In vivo antitumor activity of NVP‐BEZ235 in EEC and of DS‐7423 in OCCC cells was also observed in nude mice. We even found that the combination of a dual PI3K/mTOR inhibitor with other molecular‐targeted drugs (such as an MEK inhibitor, pimasertib) or ionizing radiation more robustly showed an anti‐tumor effect in EEC cells . Therefore, targeting PI3K/mTOR signaling is a promising strategy for these cancers.…”