Abstract A25: Evaluating a role for Rac1-PAK1 signaling in promoting the growth of KRAS-mutant pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal cancer characterized by a high frequency of activating mutations in the KRAS oncogene (95%), which is a well-validated driver of PDAC growth. With limited treatment options for this disease, there is an urgent need to better understand the aberrant signaling that occurs in order to better design therapeutic strategies. However, to date, no successful anti-K-Ras therapies have been developed. Current efforts have focused on inhibition of effectors of K-Ras signaling, in particular the Raf and PI3K effector signaling pathways. However, inhibitors targeting components of these pathways, when used as monotherapy or in combination, have been ineffectual for long-term treatment of KRAS mutant cancers. The lack of success of these inhibitors is due, in part, to the importance of other effectors in K-Ras-dependent cancer growth and the upregulation of compensatory signaling programs that overcome inhibitor activity. Consequently, in order to design effective combinatorial-targeted therapies, there is a pressing need to better understand the role of other effector signaling events that support mutant K-Ras-driven PDAC growth. The small GTPase Rac1 has a known role in driving K-Ras mutant cancers, but the specific effectors through which Rac1 promotes tumor growth have not been defined. We hypothesize that the PAK1 serine/threonine kinase, and related isoforms, PAK2 and PAK3, are key components downstream of Rac1 in mutant K-Ras PDAC. In support of this, we found that PAK1 RNA and protein levels are overexpressed in pancreatic cancer cell lines and in patient tumor samples when compared to normal tissues. Additionally we determined that stable shRNA-mediated suppression of PAK1 protein expression inhibited PDAC anchorage-independent and –dependent growth and Matrigel invasion in vitro. Further, knockdown of K-Ras in PDAC cell lines resulted in reduced phospho-PAK1 (T423) levels, indicating a decrease in PAK1 activity. We also found that a pharmacologic inhibitor of PAK1 and other Group I PAK isoforms (PAK2 and PAK3) inhibited PDAC growth. Additionally, in an RNAi kinome library screen, we identified PAK3 as a driver of resistance to pharmacologic inhibition of ERK. These observations then prompted our studies to evaluate a possible role for PAK2 and PAK3 in PDAC. Finally, our ongoing studies are evaluating the ability of Group I PAK inhibitors in combination with inhibitors of PI3K, mTORC1/2, and MEK1/2 to effectively block KRAS effector signaling and PDAC growth. Citation Format: Nicole M. Baker, Janine LoBello, Haiyong Han, Holly Yin, Jen Jen Yeh, Channing J. Der. Evaluating a role for Rac1-PAK1 signaling in promoting the growth of KRAS-mutant pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A25. doi: 10.1158/1557-3125.RASONC14-A25