E-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Alterations in phosphatidylinositol 3-kinase (PI3K) and PTEN (phosphatase and tensin homolog) are prevalent in human cancers.
• PI3Kβ is the primary isoform activated in PTEN-mutant tumors and possesses both kinase-dependent and -independent activities.

Purpose of the Study:

• To compare the efficacy of PI3Kβ depletion versus kinase inhibition in diverse tumor types and bladder cancer xenografts.
• To identify factors determining resistance to PI3Kβ downregulation.

Main Methods:

• Intratumor injection of PIK3CB siRNA for PI3Kβ depletion.
• Pharmacological inhibition of PI3Kβ kinase activity.
• Analysis of PTEN mutation, E-cadherin, and N-cadherin expression in tumor xenografts.
• Add-back experiments to assess PI3Kβ dependence.

Main Results:

• PI3Kβ depletion induced apoptosis and tumor regression more effectively than PI3Kβ inhibition in PTEN-mutant tumors.
• PTEN mutation and low E-cadherin expression were identified as necessary for PI3Kβ dependence.
• PI3Kβ depletion selectively disrupted N-cadherin cell adhesions in PTEN-mutant bladder carcinoma with E-cadherin loss.

Conclusions:

• PI3Kβ depletion via interfering RNA represents a potential therapeutic strategy for specific subsets of bladder cancer.
• This approach is particularly relevant for high-risk bladder cancers characterized by PTEN mutation and E-cadherin loss.