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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Previous research linked PTEN loss to p110β signaling dependency, driving p110β-selective inhibitor development.
• Understanding PI3K isoform dependency is crucial for effective cancer therapy.

Purpose of the Study:

• To investigate the complex regulation of PI3K isoform dependency beyond PTEN loss.
• To identify context-specific therapeutic strategies targeting the PI3K/AKT pathway.

Main Methods:

• Utilized a panel of pre-clinical cancer models.
• Analyzed PI3K isoform dependency, feedback inhibition, and PIK3CA/PIK3CB alterations.
• Evaluated efficacy of pan-PI3K, p110β-selective, AKT, and p110α-selective inhibitors.

Main Results:

• PI3K isoform dependency is influenced by feedback inhibition and concurrent PIK3CA/PIK3CB mutations, not just PTEN loss.
• IGF1R upregulation causes resistance to pan-PI3K inhibition in PTEN-deficient tumors, which can be overcome by AKT inhibition.
• In wild-type PTEN tumors with PIK3CA mutations, p110α inhibition is more effective than AKT inhibition.

Conclusions:

• PI3K isoform dependency is more nuanced than previously understood.
• Context-specific targeting of PI3K signaling nodes, such as AKT or p110α, offers improved therapeutic strategies.
• These findings pave the way for novel, tailored approaches in precision oncology.