Abstract B001: eIF2B Selectively Anchors and Activates Mutant KRAS4B

Abstract Activating mutations in KRAS occur at high frequency in colorectal, lung, and pancreatic cancers, which together account for a substantial proportion of global cancer mortality. Mutant KRAS is constitutively biased toward the GTP-bound state, driving persistent proliferative signaling, but simultaneously imposes oncogenic stresses that threaten cellular homeostasis. To sustain transformation, KRAS-mutant cells engage adaptive stress-response mechanisms, many of which converge on translational control mediated by the eIF2-eIF2B axis. While eIF2B is classically known as a guanine nucleotide exchange factor (GEF) for eIF2 during translation initiation, its potential role in directly regulating oncogenic signaling pathways has remained unexplored. Here, we identify a non-canonical function of eIF2B as a direct activator of mutant KRAS signaling. We demonstrate that eIF2B forms a tripartite complex with SOS and mutant KRAS at the plasma membrane (PM), thereby enhancing KRAS activation and tumorigenic signaling. Biochemical assays and structural modeling support an interaction between the catalytic ε subunit of eIF2B and the allosteric Ras-binding site of SOS, stabilizing SOS in an active conformation. This interaction potentiates SOS-mediated GDP/GTP exchange on mutant KRAS and promotes KRAS nanoclustering at the PM. Importantly, eIF2B exhibits marked specificity for mutant KRAS4B, but not KRAS4A, HRAS, or NRAS. This selectivity arises from KRAS4B’s unique polybasic membrane-anchoring domain and from eIF2B-dependent remodeling of plasma membrane lipid composition. eIF2B enhances glycosphingolipid (GSL) biosynthesis, particularly GM3 and SM4, through translational upregulation of B4GALT5, generating a membrane environment that preferentially supports mutant KRAS4B anchoring and signaling. Disruption of GSL synthesis impairs formation of the eIF2B:SOS:KRAS complex and selectively reduces mutant KRAS activation. Notably, eIF2B’s stimulation of mutant KRAS signaling occurs independently of eIF2α phosphorylation, separating its translational stress-response function from its oncogenic signaling role. Functionally, eIF2B promotes tumor growth specifically in KRAS-mutant cancer models, including human xenografts and an autochthonous KRAS G12C-driven lung adenocarcinoma model. Clinically, high expression of eIF2Bε correlates with poorer outcomes in patients with KRAS-mutant tumors. Our findings identify eIF2B as a previously unrecognized regulator of mutant KRAS-driven tumorigenesis that links translational control, membrane lipid remodeling, and oncogenic signaling. By coordinating SOS activation, KRAS membrane nanoclustering, and selective translation, eIF2B emerges as a central modulator of KRAS oncogenic output and a potential therapeutic and prognostic target. In vivo targeting of eIF2B supports its use as a combinatorial strategy with KRAS inhibition to broaden the therapeutic window in KRAS-mutant cancers. This abstract was edited and refined with the assistance of generative artificial intelligence to improve clarity and conciseness. Citation Format: Hyungdong Kim, Shiqi Diao, Kwang-Jin Cho, Hyun-Ro Lee, Junchen Liu, Pascal Egea, Tatu Pantsar, Milla Kurki, Nour Ghaddar, Shuo Wang, Jia Yi Zou, Mehdi Amiri, Ritchel Gannaban, John F. Hancock, Kylie M. Rice, Atsuo Sasaki, John Asara, Brajendra Tripathi, Douglas Lowy, Rosalie Lawrence, Maria Hatzoglou, Carlos R. Azpilcueta-Nicolas, Jean-Philip Lumb, John Columbus, Thomas J. Turbyville, Christopher B. Marshall, Mitsuhiko Ikura, Jay T. Groves, Nahum Sonenberg, Peter Walter, Antonis E. Koromilas. eIF2B Selectively Anchors and Activates Mutant KRAS4B [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 B001.