Abstract B078: PP2A activation drives alternative EGFR activation in PDAC

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) stands to become the 2nd most deadly cancer by 2030. Over 90% of PDAC patients have oncogenic KRAS mutations with the most prevalent being KRASG12D which have proven difficult to therapeutically target. Several studies have implicated EGFR signaling as critical for PDAC tumorigenesis in KRAS mutant tumors. Consistent with these findings, the first FDA-approved targeted therapeutic for PDAC was the EGFR inhibitor, Erlotinib. However, single agent use of Erlotinib has shown minimal efficacy in the clinic suggesting that this signaling is complex and needs further interrogation. Studies have shown the serine/threonine phosphatase, Protein Phosphatase 2A (PP2A), negatively regulates several downstream targets of EGFR and KRAS. Our previous studies using small molecule activators of PP2A demonstrate a heterogeneous response to PP2A activation, with some PDAC cell lines downregulating oncogenic signals and others maintaining the oncogenic signaling. Using pharmacological activation of PP2A, as well as overexpression and knockdown studies, we have identified a novel signaling cascade in which PP2A activation leads to increased expression and secretion of EGFR ligands and EGFR activation in a subset of PDAC cell lines. Given this unique feedback mechanism, we combined EGFR inhibitors with PP2A activation and found that the combination killed more cells than either agent alone. Together, our studies identify a novel role for PP2A in regulating EGFR signaling and support the combined use of EGFR inhibitors and PP2A activators to increase efficacy of both agents. Citation Format: Claire M. Pfeffer, Sydney J. Clifford, Elizabeth G. Hoffman, Gagan K. Mall, Garima Baral, Brittany L. Allen-Petersen. PP2A activation drives alternative EGFR activation in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B078.