Defining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers Journal Article
| Authors: | Mao, N.; Zhang, Z.; Lee, Y. S.; Choi, D.; Agudelo Rivera, A.; Li, D.; Lee, C.; Haywood, S.; Chen, X.; Chang, Q.; Xu, G.; Chen, H. A.; de Stanchina, E.; Sawyers, C.; Rosen, N.; Hsieh, A. C.; Chen, Y.; Carver, B. S. |
| Article Title: | Defining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers |
| 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. © 2021, The Author(s). |
| Journal Title: | Nature Communications |
| Volume: | 12 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2021-08-20 |
| Start Page: | 5053 |
| Language: | English |
| DOI: | 10.1038/s41467-021-25341-9 |
| PROVIDER: | scopus |
| PUBMED: | 34417459 |
| PMCID: | PMC8379232 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 September 2021 -- Source: Scopus |
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