Synergistic Inhibition of PI3K and HSP90 Enhanced Antitumorigenic Efficacy in Adrenocortical Carcinoma

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Adrenocortical cancer (ACC) is a rare, aggressive malignancy with limited effective treatment options.
• Identifying novel therapeutic strategies is crucial for improving patient survival and facilitating clinical trials.
• Drug combination screening is a key approach to discover synergistic anticancer effects.

Purpose of the Study:

• To identify synergistic drug combinations for adrenocortical cancer (ACC) treatment.
• To validate the efficacy of combined phosphatidylinositol-3-kinase (PI3K) and heat shock protein 90 (HSP90) inhibitors in preclinical ACC models.
• To explore the mechanisms of action and potential clinical applicability of promising drug combinations.

Main Methods:

• Quantitative high-throughput drug screening to identify synergistic combinations.
• Preclinical in-vitro studies using ACC cell lines and 3D organoids.
• In-vivo studies using human ACC xenografts.
• RNA sequencing and phenotypic analysis to elucidate mechanisms of cell death.

Main Results:

• Synergy was identified between PI3K inhibitors (PIK75, BGT226) and HSP90 inhibitors (Ganetespib/STA9090).
• The PIK75-STA9090 combination inhibited proliferation, migration, and epithelial-to-mesenchymal transition, inducing apoptosis and cell cycle arrest.
• The BGT226-STA9090 combination induced autophagy-related cell death and demonstrated significant antitumor efficacy in xenografts and patient-derived organoids (PDOs).

Conclusions:

• Combinations of PI3K and HSP90 inhibitors exhibit potent synergistic efficacy against ACC in preclinical settings.
• The BGT226-STA9090 combination represents a clinically viable therapeutic strategy for advanced ACC.
• These findings support the initiation of clinical trials to evaluate the efficacy of PI3K and HSP90 inhibitor combinations in patients with advanced ACC.