Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced AKI

Area of Science:

• Pharmacology
• Nephrology
• Ototoxicology

Background:

• Cisplatin is a vital chemotherapy drug but causes dose-limiting nephrotoxicity and ototoxicity.
• No FDA-approved drugs currently treat both cisplatin-induced kidney damage and hearing loss.
• AZD5438 (CDK2 inhibitor) and dabrafenib (BRAF inhibitor) previously protected against cisplatin-induced hearing loss in mice.

Purpose of the Study:

• To investigate the potential of AZD5438 and dabrafenib in alleviating cisplatin-induced acute kidney injury (AKI).
• To determine if shared cellular pathways are involved in cisplatin-induced kidney and inner ear damage.
• To evaluate the efficacy of these drugs in a mouse model of cisplatin-induced AKI.

Main Methods:

• Utilized the HK-2 cell line and FVB mice to assess drug protection against cisplatin-induced cell death and AKI.
• Analyzed serum biomarkers (BUN, creatinine, NGAL) and kidney histopathology.
• Examined markers of kidney cell death (necroptosis, pyroptosis) and proliferation (pERK, PCNA) via Western blotting and immunofluorescence.
• Employed CDK2 knockout mice to confirm AZD5438's mechanism of action.

Main Results:

• AZD5438 and dabrafenib reduced cisplatin-induced cell death in HK-2 cells and attenuated AKI in mice.
• Both drugs decreased serum kidney injury markers and inhibited cell death pathways.
• Reduced levels of pERK and PCNA correlated with enhanced animal survival.
• CDK2 knockout mice exhibited resistance to cisplatin-induced AKI, with AZD5438 providing no additional benefit.

Conclusions:

• Cisplatin-induced damage to the kidneys and inner ear exhibits similar cellular responses to AZD5438 and dabrafenib.
• These findings highlight the potential therapeutic utility of AZD5438 and dabrafenib for managing both cisplatin-induced nephrotoxicity and ototoxicity.