Czyzyk Daniel, Yan Wupeng, Messing Simon, Gillette William, Tsuji Takashi, Yamaguchi Mitsuhiro, Furuzono Shinji, Turner David M, Esposito Dominic, Nissley Dwight V, McCormick Frank, Simanshu Dhirendra K
NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
Nat Commun. 2025 Jan 9;16(1):525. doi: 10.1038/s41467-024-55766-x.
Mutations in RAS and PI3Kα are major drivers of human cancer. Their interaction plays a crucial role in activating PI3Kα and amplifying the PI3K-AKT-mTOR pathway. Disrupting RAS-PI3Kα 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 (p110α) of PI3Kα, elucidating the interaction interfaces and local conformational changes upon complex formation. Structural and mutational analyses highlighted key residues in RAS and PI3Kα 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-p110α complex structures, RAS interaction with p110α is limited to the RAS-binding domain and does not involve the kinase domain. This study underscores the pivotal role of the RAS-PI3Kα interaction in PI3Kα activation and provides a blueprint for designing PI3Kα isoform-specific inhibitors to disrupt this interaction.
RAS和PI3Kα中的突变是人类癌症的主要驱动因素。它们的相互作用在激活PI3Kα和放大PI3K-AKT-mTOR信号通路中起着关键作用。破坏RAS-PI3Kα相互作用可提高肺癌和皮肤癌模型中的生存率，并减少肿瘤生长和血管生成，尽管这种相互作用的结构细节仍不清楚。在这里，我们展示了与PI3Kα催化亚基（p110α）结合的KRAS、RRAS2和MRAS的结构，阐明了相互作用界面以及复合物形成时的局部构象变化。结构和突变分析突出了RAS和PI3Kα中影响结合亲和力的关键残基，并揭示了RAS和PI3K亚型相互作用界面上的亚型特异性差异，为它们的不同亲和力提供了理论依据。值得注意的是，在RAS-p110α复合物结构中，RAS与p110α的相互作用仅限于RAS结合结构域，不涉及激酶结构域。这项研究强调了RAS-PI3Kα相互作用在PI3Kα激活中的关键作用，并为设计破坏这种相互作用的PI3Kα亚型特异性抑制剂提供了蓝图。
