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Publication Abstract from PubMed

Mutations in RAS and PI3Kalpha are major drivers of human cancer. Their interaction plays a crucial role in activating PI3Kalpha and amplifying the PI3K-AKT-mTOR pathway. Disrupting RAS-PI3Kalpha interaction enhances survival in lung and skin cancer models and reduces tumor growth and angiogenesis, although the structural details of this interaction remain unclear. Here, we present structures of KRAS, RRAS2, and MRAS bound to the catalytic subunit (p110alpha) of PI3Kalpha, elucidating the interaction interfaces and local conformational changes upon complex formation. Structural and mutational analyses highlighted key residues in RAS and PI3Kalpha impacting binding affinity and revealed isoform-specific differences at the interaction interface in RAS and PI3K isoforms, providing a rationale for their differential affinities. Notably, in the RAS-p110alpha complex structures, RAS interaction with p110alpha is limited to the RAS-binding domain and does not involve the kinase domain. This study underscores the pivotal role of the RAS-PI3Kalpha interaction in PI3Kalpha activation and provides a blueprint for designing PI3Kalpha isoform-specific inhibitors to disrupt this interaction.

Structural insights into isoform-specific RAS-PI3Kalpha interactions and the role of RAS in PI3Kalpha activation.,Czyzyk D, Yan W, Messing S, Gillette W, Tsuji T, Yamaguchi M, Furuzono S, Turner DM, Esposito D, Nissley DV, McCormick F, Simanshu DK Nat Commun. 2025 Jan 9;16(1):525. doi: 10.1038/s41467-024-55766-x. PMID:39788953^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.