p21-activated kinases (PAKs) are Cdc42/Rac-activated serine-threonine protein kinases that regulate several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt, and Wnt/b-catenin. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including human breast, ovary, prostate, and brain cancer, due to amplification of the PAK1 gene in an 11q13 amplicon. In our previous in vitro and in vivo studies we have shown that ovarian cancer cells with amplified/overexpressed Pak1 were significantly more sensitive to pharmacologic or genetic inhibition of Pak1 compared to cells without 11q13 amplification. In the present study we examined the combination effect of the Pak1 inhibitor FRAX1036 in ovarian cancer cells using ICCB Known Bioactives Library (Enzo). We found that the cytotoxic effect of FRAX1036 was significantly higher when combined with the PKC delta inhibitor, Rottlerin.
We tested FRAX1036 alone and in combination with Rottlerin on 11q13-amplified human ovarian cancer cell lines with respect to cell proliferation, migration and apoptosis. FRAX1036 alone inhibited cell proliferation and migration in 11q13-amplified ovarian cancer cell lines. Co-administration of FRAX1036 with Rottlerin further synergized the inhibition of cell proliferation in vitro and decreased tumor growth in vivo. To explain the synergistic inhibition of cell proliferation induced by the FRAX1036/Rottlerin combination we analyzed Pak1 and PKC delta down-stream signaling molecules. Western blot data indicated that FRAX1036 and Rottlerin synergistically inhibited phosphorylation of critical signaling molecules such as MEK, ERK1/2, b-Catenin, and 4EBP1.
Our findings suggest that Pak1 small molecule inhibitors in combination with Rottlerin hold potential clinical value as chemotherapeutic drugs for the ∼25% of ovarian cancers characterized by PAK1 gene amplification.
Citation Format: Tatiana Prudnikova, Jonathan Chernoff. PAK1 inhibitor FRAX1036 sensitizes ovarian cancer cells with amplified 11q13 to cytotoxic effect of rottlerin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-011.