The 'New (Nu)-clear' evidence for the tumor-driving role of PI3K

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• The phosphatidylinositol 3-kinase (PI3K) pathway is crucial in cell signaling and frequently dysregulated in cancer.
• PIK3CA mutations, particularly in the helical and kinase domains, are common oncogenic drivers in various human cancers.
• Distinct phenotypes arise from different PIK3CA mutation types, but the underlying mechanisms are not fully understood.

Purpose of the Study:

• To investigate the role of the PI3K p85β regulatory subunit in cancers with PIK3CA helical domain mutations.
• To elucidate the mechanism by which p85β influences tumor progression in these specific cancer types.
• To identify potential therapeutic strategies targeting PIK3CA helical mutation-driven cancers.

Main Methods:

• Analysis of p85β localization in cancer cells with different PIK3CA mutations.
• In vivo studies using mouse models to assess the impact of p85β nuclear translocation on tumor growth.
• Investigation of the molecular interactions of nuclear p85β, including recruitment of USP7 and stabilization of EZH1/2.
• Combination therapy studies using PI3K and EZH inhibitors in xenograft models.

Main Results:

• The PI3K p85β regulatory subunit dissociates from the PI3K complex and translocates to the nucleus specifically in cancer cells with PIK3CA helical domain mutations.
• Suppression of p85β nuclear localization significantly inhibited tumor growth in mouse models of PIK3CA helical mutation-driven cancer.
• Nuclear p85β was found to recruit USP7, which stabilizes EZH1/2, leading to increased H3K27 trimethylation and altered gene transcription.
• Combined inhibition of PI3K and EZH resulted in the regression of xenograft tumors harboring PIK3CA helical domain mutations.

Conclusions:

• The PI3K p85β regulatory subunit plays a previously unrecognized role in promoting cancer progression driven by PIK3CA helical domain mutations.
• Nuclear localization of p85β is a key mechanism driving tumor growth through the USP7-EZH1/2 axis.
• Targeting nuclear p85β or employing combination therapy with PI3K and EZH inhibitors represents a promising therapeutic strategy for PIK3CA helical mutation-positive cancers.