Defining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers

Ninghui Mao, Zeda Zhang, Young Sun Lee, Danielle Choi, Aura Agudelo Rivera, Dan Li, Cindy Lee, Samuel Haywood, Xiaoping Chen, Qing Chang, Guotai Xu, Hsuan-An Chen, Elisa Stanchina, Charles Sawyers, Neal Rosen, Andrew C. Hsieh, Yu Chen and Brett S. Carver ()
Additional contact information
Ninghui Mao: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Zeda Zhang: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Young Sun Lee: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Danielle Choi: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Aura Agudelo Rivera: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Dan Li: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Cindy Lee: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Samuel Haywood: Memorial Sloan Kettering Cancer Center
Xiaoping Chen: Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center
Qing Chang: Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center
Guotai Xu: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Hsuan-An Chen: Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center
Elisa Stanchina: Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center
Charles Sawyers: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Neal Rosen: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center
Andrew C. Hsieh: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center
Yu Chen: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Brett S. Carver: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25341-9

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