Defining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers.
| Publication Type | Academic Article |
| Authors | Mao N, Zhang Z, Lee Y, Choi D, Rivera A, Li D, Lee C, Haywood S, Chen X, Chang Q, Xu G, Chen H, de Stanchina E, Sawyers C, Rosen N, Hsieh A, Chen Y, Carver B |
| Journal | Nat Commun |
| Volume | 12 |
| Issue | 1 |
| Pagination | 5053 |
| Date Published | 08/20/2021 |
| ISSN | 2041-1723 |
| Keywords | Phosphatidylinositol 3-Kinases, Prostatic Neoplasms, Signal Transduction |
| Abstract | Previous studies have suggested that PTEN loss is associated with p110β signaling dependency, leading to the clinical development of p110β-selective inhibitors. Here we use a panel pre-clinical models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner. |
| DOI | 10.1038/s41467-021-25341-9 |
| PubMed ID | 34417459 |
| PubMed Central ID | PMC8379232 |