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 often hindered by the development of resistance driven by disrupted negative feedback mechanisms led by phosphatases like 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 RAS/MAPK inhibitor to restore PP2A activity and counteract resistance. We demonstrated that KRASG12C and MEK1/2 inhibitors disrupted PP2A carboxymethylation and destabilized critical heterotrimeric complexes. Furthermore

SUBMITTER: Raines B 

PROVIDER: S-EPMC12646674 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature