PI3K Driver Mutations: A Biophysical Membrane-Centric Perspective

Ras activates its effectors at the membrane. Active PI3K alpha and its associated kinases/phosphatases assemble at membrane regions enriched in signaling lipids. In contrast, the Raf kinase domain extends into the cytoplasm and its assembly is away from the crowded membrane surface. Our structural membrane-centric outlook underscores the spatiotemporal principles of membrane and signaling lipids, which helps clarify PI3K alpha activation. Here we focus on mechanisms of activation driven by PI3K alpha driver mutations, spotlighting the PI3K alpha double (multiple) activating mutations. Single mutations can be potent, but double mutations are stronger: their combination is specific, a single strong driver cannot fully activate PI3K, and two weak drivers may or may not do so. In contrast, two strong drivers may successfully activate PI3K, where one, for example, H1047R, modulates membrane interactions facilitating substrate binding at the active site (km) and the other, for example, E542K and E545K, reduces the transition state barrier (ka), releasing autoinhibition by nSH2. Although mostly unidentified, weak drivers are expected to be common, so we ask here how common double mutations are likely to be and why PI3K alpha with double mutations responds effectively to inhibitors. We provide a structural view of hotspot and weak driver mutations in PI3K alpha activation, explain their mechanisms, compare these with mechanisms of Raf activation, and point to targeting cell-specific, chromatin-accessible, and parallel (or redundant) pathways to thwart the expected emergence of drug resistance. Collectively, our biophysical outlook delineates activation and highlights the challenges of drug resistance.

Automated summary

This study focuses on the activation mechanisms of PI3Kα, particularly driven by double activating mutations. It highlights the importance of strong driver mutations in fully activating PI3K, as single strong drivers may not be sufficient. In contrast, double strong drivers can effectively activate PI3K, and interactions between different driver mutations play a critical role in the activation process.