Abstract A043: Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation

Abstract Oncogenic mutations in KRAS and NRAS are key drivers of hematological malignancies; however, direct pharmacologic targeting of RAS proteins remains a major therapeutic challenge. To identify previously unrecognized RAS regulatory mechanisms and vulnerabilities, we integrated genome-wide CRISPR–Cas9 screening, spatial proteomics, and biochemical interrogation of RAS stability pathways. Our studies reveal that the phosphatase PP1C directly dephosphorylates the conserved T148 residue on KRAS and NRAS, an event that enables E3 ligase LZTR1-mediated proteasomal degradation of RAS. Importantly, we demonstrate that oncogenic KRAS A146 mutations—a gain-of-function class enriched in hematologic cancers and positioned adjacent to T148—impede this degradation process. We further identify PAK1 as the kinase that counteracts PP1C by phosphorylating T148, thereby stabilizing RAS and preventing its turnover. Collectively, these findings define a previously uncharacterized PP1C–PAK1–RAS–LZTR1 regulatory axis that governs RAS protein stability and represents a therapeutically exploitable vulnerability in RAS-dependent blood cancers. Consistent with this notion, combined PAK1/2 inhibition and RAS pathway blockade synergistically impairs the viability of RAS-dependent myeloma and leukemia cells in vitro and suppresses RAS-driven tumor growth in vivo. Together, our work delineates a novel, mechanistically coherent regulatory circuit controlling RAS stability and highlights an actionable intervention point for treating RAS-driven hematologic malignancies. Citation Format: Lin Zhang, Arnold Bolomsky, Omar Al-Odat, Callie Van. Winkle, Aaliyah Battle, Papiya Chakraborty, Ronald J. Holewinski, Thorkell Andresson, Qingcai Meng, James D. Phelan, Jagan Muppidi, Ryan M. Young. Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation [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 A043.