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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MSK Authors
  1. Charles L Sawyers
    225 Sawyers
  2. Neal Rosen
    425 Rosen
  3. Yu Chen
    133 Chen
  4. Brett Stewart Carver
    143 Carver
  5. Qing Chang
    36 Chang
  6. Xiaoping Chen
    11 Chen
  7. Zeda Zhang
    18 Zhang
  8. Ninghui   Mao
    19 Mao
  9. Dan Li
    16 Li
  10. Guotai Xu
    14 Xu
  11. Hsuan An Chen
    9 Chen
  12. Danielle Wai-pui Li
    12 Li
  13. Young Sun Lee
    11 Lee
  14. Cindy J Lee
    18 Lee