Abstract PR014: A PP2A molecular glue overcomes RAS/MAPK inhibitor resistance in KRAS-mutant non–small cell lung cancer

Abstract The effectiveness of RAS/MAPK inhibitors in treating metastatic KRAS-mutant non–small cell lung cancer (NSCLC) is oftenhindered by the development of resistance driven by disrupted negative feedback mechanisms led by phosphatases likethe serine threonone phospahatase PP2A. PP2A is frequently suppressed in lung cancer to maintain elevated RAS/MAPK activity. Despite its established role in regulating oncogenic signaling, targeting PP2A with RAS/MAPK to prevent resistance has not been previously demonstrated. In this study, we aimed to establish a treatment paradigm by combining a PP2A molecular glue with a series of RAS/MAPK inhibitors to restore PP2A activity and counteract resistance. We demonstrated that KRASG12C and MEK1/2 inhibitors disrupted PP2A carboxymethylation and destabilized critical heterotrimeric complexes. Furthermore, genetic disruption of PP2A carboxymethylation enhanced intrinsic resistance to MEK1/2 inhibition both in vitro and in vivo. We developed RPT04402, a PP2A molecular glue that selectively stabilizes PP2A-B56α heterotrimers. In commercial cell lines and in patient-derived model, combining RPT04402 with a RAS/MAPK inhibitor slowed proliferation and enhanced apoptosis. In mouse xenografts. This targeted drug combination induced tumor regressions and even complete responses that were durable to 150 days after initiation of treatment, extended median survival, and delayed the onset of treatment resistance. Furthermore, these PP2A molecular glues were able to overcome intrinsic resistance in preclinical NSCLC KRAS driven models. Important;y, we have identified a development candidate SW-3431, which is a first-in-class molecular glue for the potential clinical translation of these observations in the near term. Collectively, these findings highlight that promoting PP2A stabilization and RAS/MAPK inhibition presents a promising therapeutic strategy to improve treatment outcomes and overcome resistance in metastatic KRAS-mutant NSCLC. Citation Format: Goutham Narla, Brynne Raines, Caitlin M. O'Connor. A PP2A molecular glue overcomes RAS/MAPK inhibitor resistance in KRAS-mutant non–small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr PR014.