Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced Acute Kidney Injury

Background: Cisplatin is an effective chemotherapy agent for a wide variety of solid tumors, but its use is dose-limited by serious side effects including acute kidney injury (AKI) and hearing loss. There are no FDA-approved drugs to treat both side effects. Recently, two anti-cancer oral drugs, AZD5438 and dabrafenib, were identified as protective against cisplatin-induced hearing loss in mice. We hypothesize that similar cell stress and death pathways are activated in kidney and inner ear cells when exposed to cisplatin, and tested whether these drugs alleviate cisplatin-induced AKI.

Methods: The HK-2 cell line and adult FVB mice were utilized to measure the protection from cisplatin-induced cell death and AKI by these drugs. Serum markers of kidney injury, BUN, creatinine, and NGAL, as well as histology of kidneys were analyzed. Levels of markers of kidney cell death including Necroptosis and Pyroptosis, PERK, and PCNA, were also examined by western blotting and immunofluorescence. Additionally, CDK2 KO mice were utilized to confirm AZD5438 protective effect is through CDK2 inhibition.

Results: The drugs reduced cisplatin-induced cell death in the HK-2 cell line and attenuated cisplatin-induced AKI in mice. The drugs reduced serum kidney injury markers, inhibited cell death, and reduced levels of PERK and PCNA, all of which correlated with prolonged animal survival. CDK2 KO mice were resistant to cisplatin-induced AKI and AZD5438 conferred no additional protection in the KO mice.

Conclusion: Cisplatin-induced damage to the inner ear and kidneys share similar cellular beneficial responses to AZD5438 and dabrafenib highlighting the potential therapeutic use of these agents to treat both cisplatin-mediated kidney damage and hearing loss.