Abstract B066: Unique roles of group I PAK isoforms in regulating MPNST cell viability

Abstract

Abstract Group I p21-activated kinases (PAKs) include three members (PAK1, PAK2, and PAK3) that represent key components of several cell signaling networks. By transmitting growth factor-induced signals from Rho family GTPases, PAK1/2/3 regulate cytoskeletal dynamics, cell shape, and motility. Group I PAKs modulate several oncogenic and survival pathways and are thought to play a critical role in initiation and progression of certain tumor types. Although group I PAK members share significant sequence similarity, mechanism of regulation, and substrates, PAK isoforms show different gene expression patterns in tissues and play unique functions in development and immune responses. While the described PAK1/2/3 functions in tumorigenesis are generally assigned to PAK1, there are increasing hints of isoform-specific roles for group I PAKs in cancer. We have recently demonstrated that PAK1/2/3 signaling is upregulated in malignant peripheral nerve sheath tumors (MPNSTs) and that small-molecule PAK inhibitors suppress MPNST growth and dissemination. The selective group I PAK inhibitors (Frax1036 and GST-PID) tested in this study target all three isoforms and exhibit moderate effects on MPNST cell viability as single agents. We have now used an RNAi approach to knock down individual group I PAK isoforms and their combinations to show that PAK1 and PAK3 knockdown inhibits MPNST cell proliferation, while PAK2 knockdown does not impede the growth of most MPNST cell lines, and in some cases, augments it. Interestingly, combined depletion of PAK1/2/3 has less profound cytotoxic effects compared to single knockdowns of PAK1 or PAK3, suggesting the potential need for isoform-selective PAK inhibitors as therapeutic agents for MPNSTs. Citation Format: Galina Semenova, Dina Stepanova, Sofiia Karchugina, Cara Dubyk, Sergey Deyev, Alexander Lazar, Jonathan Chernoff. Unique roles of group I PAK isoforms in regulating MPNST cell viability [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B066.