SETD2 loss sensitizes cells to PI3Kβ and AKT inhibition

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• The phosphatidylinositol 3-kinase (PI3K) pathway is frequently upregulated in renal cell carcinoma (RCC), driving cancer initiation and progression.
• Current targeted therapies for advanced RCC offer limited durable responses, highlighting the need for novel biomarker-driven treatment strategies.
• Loss of the SETD2 methyltransferase is observed in a subset of clear cell RCC (ccRCC) cases.

Purpose of the Study:

• To investigate the potential synthetic lethal interaction between phosphatidylinositol 3-kinase beta (PI3Kβ) inhibition and loss of SETD2 function in ccRCC.
• To evaluate the efficacy of PI3Kβ-specific inhibitors in preclinical models of SETD2-deficient ccRCC.

Main Methods:

• Utilized SETD2 knockout and proficient ccRCC cell lines (786-0 and A498).
• Treated cells with PI3Kβ-specific inhibitors (TGX221, AZD8186) and downstream AKT inhibitor (MK2206).
• Assessed cell viability, growth, migration, and tumor growth in vivo.

Main Results:

• PI3Kβ inhibition (TGX221, AZD8186) significantly reduced viability, growth, and migration in SETD2-deficient ccRCC cells compared to SETD2-proficient cells.
• AZD8186 treatment markedly decreased tumor growth in vivo for SETD2-mutant A498 cells, but not for SETD2-proficient 786-0 cells.
• Inhibition of the downstream AKT pathway mimicked the effects of PI3Kβ inhibition in SETD2-deficient cells.

Conclusions:

• Specific inhibition of PI3Kβ exhibits synthetic lethality in ccRCC cells with loss of SETD2.
• Targeting the AKT pathway downstream of PI3Kβ presents a viable therapeutic strategy for SETD2-deficient ccRCC.
• These findings support further clinical investigation of PI3Kβ-specific inhibitors in ccRCC patients with SETD2 alterations.