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0This research identifies how cancer cells develop resistance to tri-complex inhibitors (TCIs), which are molecular glues designed to neutralize oncogenic RAS signaling. By analyzing patient samples and preclinical models, the authors discovered that specific mutations disrupt the RAS-inhibitor-CYPA synthetic complex. Some alterations, like those at KRAS residue Y64, physically prevent the drug from binding to the RAS protein. Conversely, mutations such as KRAS Y71H or hypoactive BRAF increase the natural affinity between RAS and its effectors, making it harder for the drug to displace them. The study highlights these convergent resistance pathways to inform the development of next-generation inhibitors and better combination therapies. These findings provide a structural and mechanistic framework for overcoming evasion strategies in RAS-driven malignancies.
References:
Sang B, Ye L, Fu Z ... Disrupted molecular glue complex drives RAS inhibitor resistance. Cell, 2026; 0
