Targeting a novel covalent RAS dimer in RASQ61 mutants-driven cancers

(30 line limit) RAS mutations drive a substantial proportion (20~30%) of deadly tumors. Two KRASG12C inhibitors, sotorasib and adagrasib, are now approved, justifying the feasibility of direct targeting RAS. Despite this achievement, approved KRASG12C inhibitors do not address other oncogenic RAS alleles, such as the hotspot Q61 mutations (e.g. Q61H, Q61K, Q61L, and Q61R). Thus, a deeper understanding of fundamental RAS mechanisms and functions is essential for effectively tackling RAS-driven diseases. RAS transmits signals through protein-protein interactions controlled by nucleotide binding state. These interactions are thought to occur within multi- component "signalosomes" that form when RAS is bound to the cell membrane and various RAS effector proteins. We have published two structural models (Cell and Nat Struct Mol Biol) for membrane-bound KRAS protein complexes, validated in biological systems, while other models have been proposed without biological validation yet. The transient nature of these “complexes,” makes them difficult to isolate and study. This proposal aims to characterize the novel, covalent RAS dimer we have observed at the hotspot Q61, and to develop new therapeutic strategies specifically targeting RASQ61 mutants commonly found in human cancers, such as melanoma, leukemia, thyroid cancer, and lung cancer. Based on our preliminary data, we hypothesize that RASQ61 mutants form covalent dimer at differential propensity and are particularly responsive to specific classes of RAF and MEK inhibitors. Therefore, the specific aims of the current proposal are to 1) Determine the prevalence and determinants of the covalent dimer of RASQ61 mutants; 2) Evaluate the impact of RAFi’s and MEKi’s on covalent RAS dimer formation and signaling of RASQ61 mutants; 3) Elucidate the mechanism for RAFi’s and MEKi’s sensitivity in the context of RASQ61 mutants. The overarching goal of this proposal is to develop new therapeutic concepts specifically tailored to RASQ61 mutants (Q61H, Q61K, Q61L, and Q61R) found in cancer patients. Successful completion of this study will characterize Cys118-meidated covalent RAS dimer of Q61 mutants and pinpoint the best RAFi’s and MEKi’s for RASQ61 mutants-driven cancers. This research will set the stage for clinical development of the first RAS biomarker-driven, molecularly targeted RAFi and MEKi therapies, representing a significant and innovative advancement in clinical oncology given the current lack of targeted therapies for RASQ61 mutants-driven cancers. More broadly, this work will expand our fundamental knowledge of how RAS proteins function within larger signaling complexes at the cell membrane. Project Number: 1K01CA313805-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Zhiwei Zhou | Institution: UT SOUTHWESTERN MEDICAL CENTER, DALLAS, TX | Award Amount: $131,727 | Activity Code: K01 | Study Section: Special Emphasis Panel[ZRG1 CDPT-P (56)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11351438