Abstract 2644: Inhibition of PAK4 attenuates renal cell carcinoma (RCC) growth

Abstract

Abstract Renal cell carcinoma (RCC) is an increasingly prevalent cancer type that is frequently asymptomatic on presentation and is associated with poor responses and resistance even to the current targeted therapies. Thus, novel therapeutic approaches to treat this disease are urgently needed. P21-activated kinase 4 (PAK4) is a mediator of filopodia formation and stabilizes β-catenin transcriptional activity. PAK4 lies in a pathway integral to both nephrogenesis and cancer. We hypothesized that inhibitors of the PAK4 signaling pathway would result in salutary effects on RCC. To test this, we evaluated the in vitro response of RCC cells to the specific PAK4 Allosteric Modulators (PAMs; KPT-8752 and KPT-9274). Similar to cells of other cancer types, 786-O (VHL-mutant RCC) showed decreases of both Phospho-PAK4 and Phospho-β-catenin after 24 h of incubation with 10 μM KPT-8752. In addition, both 786-O and ACHN (VHL-wildtype RCC cells) showed a marked time-dependent decrease in cell viability from 24 to 72 h of incubation from 2 to 10 μM of KPT-8752. KPT-9274 was orally administered at 25 and 100 mg/kg twice a day for 5 days/week to Caki-1 (VHL-wildtype RCC) and 786-O subcutaneous nude mouse xenograft models. In these studies the tumor growth rate was attenuated at both doses in the 786-O cells and at the higher dose for Caki-1 cells. There was no obvious change in the health of any of the animals suggesting manageable tolerability. We are currently evaluating combination therapy in our laboratory. In summary, PAK4 inhibitors show considerable promise as novel treatments of RCC as a single agent and warrant further investigation. Citation Format: Omran Abu Aboud, William Senapedis, Yosef Landesman, Erkan Baloglu, Robert H. Weiss. Inhibition of PAK4 attenuates renal cell carcinoma (RCC) growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2644. doi:10.1158/1538-7445.AM2015-2644