Abstract PR010: ERK hyperactivation-induced lethality as a therapeutic strategy in RAS-driven tumors

Abstract The MAPK pathway is essential for driving cell proliferation and survival and frequently harbors mutations along its signaling axis in multiple tumor subtypes. Previous studies have shown that an optimal level of MAPK signaling is required to drive oncogenesis; too weak of signaling fails to drive cellular transformation, while too strong of signaling results in oncogene-induced senescence and cellular toxicity. Decades of research targeting RAS and MAPK pathway inhibition have yielded potent clinical drugs that show robust efficacy in subsets of KRAS mutant or BRAF mutant tumors. Efficacy observed with these targeted treatments is typically driven by durable MAPK pathway inhibition, which results in potent suppression of ERK phosphorylation and the requisite transcriptional programs downstream that drive tumor growth and proliferation. Importantly, the clinical efficacy observed to date is not durable despite achieving initial responses and most patients progress due to a range of bypass mechanisms including RAS amplification, MAPK pathway mutations and other mechanisms which render the pathway back on. We hypothesized rather than inhibit the MAPK pathway to drive long term efficacy, we could induce potent cell death through oncogene-induced lethality. We previously developed a novel small molecule that binds to the DEF domain of ERK, which displaces negative regulators and induces ERK hyperactivation and induces cell death in the context of BRAFV600E mutant tumors. This hyperactivation of ERK results in increased cellular stress and apoptosis in vitro. We asked whether we could apply this same approach to the context of RAS mutant tumors. Using our ERK-DEF inhibitor, we conducted a series of mechanistic experiments delineating the pathway output upon pathway activation. Synthetic lethal CRISPR based screens in the presence of the ERK-DEF inhibitor in KRAS mutant tumors cells uncover additional approaches for combinations with ERK-DEF inhibitors in RAS mutant tumors. This study highlights oncogene activation-driven lethality as a viable therapeutic strategy for MAPK-driven tumors. Citation Format: Alexa C. Cannon, Sara Scardocci, Young Lee, Ribo Guo, Eiru Kim, David Ruddy, Shiva Malek, Vesselina Cooke. ERK hyperactivation-induced lethality as a therapeutic strategy in RAS-driven tumors [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 PR010.