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
DOI/URL:
Notes: Article -- Export Date: 1 September 2021 -- Source: Scopus
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MSK Authors
  1. Charles L Sawyers
    199 Sawyers
  2. Neal Rosen
    399 Rosen
  3. Yu Chen
    96 Chen
  4. Brett Stewart Carver
    131 Carver
  5. Qing Chang
    19 Chang
  6. Xiaoping Chen
    5 Chen
  7. Zeda Zhang
    12 Zhang
  8. Ninghui   Mao
    15 Mao
  9. Dan Li
    6 Li
  10. Guotai Xu
    14 Xu
  11. Hsuan An Chen
    6 Chen
  12. Danielle Wai-pui Li
    12 Li
  13. Young Sun Lee
    10 Lee
  14. Cindy J Lee
    4 Lee