Abstract 3799: The PAK4 allosteric modulator (KPT-9274) attenuates the growth of renal cell carcinoma

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, both of which are integral to 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 several human RCC cells and normal kidney proximal epithelial cells (NHKs) to the specific PAK4 Allosteric Modulators (PAMs; KPT-8752 and KPT-9274). 786-O (VHL-mutant RCC) and caki-1 (VHL-wt RCC) cells showed decreases in cell viability (MTT), induction of apoptosis and arrest in G2/M phase when incubated with these inhibitors. These responses were diminished in NHK cells which served as a “normal” control cell line. Target and specific pathway proteins (phospho-PAK4, Phospho-β-catenin, c-Myc and cyclin D1) were reduced after RCC, but not NHK, were incubated with KPT-8752 and KPT-9274. To confirm specificity of the inhibitor to PAK4, all these responses were reproduced in RCC cells using specific PAK4 siRNA. Since ∼85% of RCC cases are associated with mutation in vhl we used 786-0 xenograft mouse model to evaluate the clinical candidate KPT-9274. KPT-9274 was orally administered at 100 and 200 mg/kg BIDX5 for 4 weeks, resulting in clear attenuation of tumor growth at both doses. There was no obvious change in the health or weight of any of the animals when compared to vehicle group suggesting manageable tolerability. We are currently evaluating combination therapy and plan to test this inhibitor on a metastatic RCC model. In summary, PAK4 inhibitors show considerable promise as novel treatments of RCC as a single agent and warrants further investigation. Citation Format: Robert H. Weiss, Omran Abu Aboud, Erkan Baloglu, William Senapedis, Sharon Shacham. The PAK4 allosteric modulator (KPT-9274) attenuates the growth of renal cell carcinoma. [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 3799.