Repurposing AZD5438 and Dabrafenib for Cisplatin-Induced AKI

Abstract

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.

KSR1 knockout mouse model demonstrates MAPK pathway's key role in cisplatin- and noise-induced hearing loss

“…Overactivation of the MAPK pathway, as observed with cisplatin and noise exposure in the inner ear, can lead to downstream cellular stress pathways and eventually to cell death and dysfunction ( Lahne and Gale, 2008 ; Ohori, 2008 ; Cagnol and Chambard, 2010 ; Alagramam et al, 2014 ; Herranen et al, 2018 ; Ingersoll et al, 2020 ). Stimulation of the MAPK pathway has previously been associated with cell survival and proliferation; however, our studies here and previous studies have suggested that this pathway can also act as a cellular stress pathway in some nonproliferating cells such as the inner ear and the kidney ( Jo et al, 2005 ; Ingersoll et al, 2020 , 2023 ; Pushpan et al, 2024 ). Following cisplatin and noise exposure, there is a significant increase in ROS, proinflammatory cytokines and chemokines, and other inflammatory markers, which are all markers of cell stress ( Dhukhwa et al, 2019 ; Ramkumar et al, 2021 ; Al Aameri et al, 2023 ; Wang et al, 2023 ).…”

“…Activation of the MAPK pathway as a stress pathway following various damaging stimuli could be a general cell stress pathway that is activated in different postmitotic cells, not just the inner ear cells. Other studies, including ours, have shown that activation of MAPK proteins in other tissues, such as the kidneys and neurons, leads to cellular stress and death ( Jo et al, 2005 ; Ohori, 2008 ; Xu et al, 2016 ; Pucilowska et al, 2018 ; Liu et al, 2022 ; Pushpan et al, 2024 ). This current study contributes further evidence that the MAPK pathway can act as a stress response pathway and targeting the proteins in the pathway could be beneficial for preventing other types of diseases such as acute kidney injury and neuroinflammatory disorders ( Jo et al, 2005 ; Ohori, 2008 ; Cagnol and Chambard, 2010 ; Liu et al, 2022 ; Pushpan et al, 2024 ).…”

ERK1/2 Inhibition via the Oral Administration of Tizaterkib Alleviates Noise-Induced Hearing Loss While Tempering down the Immune Response

“…The activation of ERK can also affect immune cell migration, so ERK inhibition could be directly inhibiting the migration of immune cells to the cochlea following noise insult [ 86 , 87 ]. It is interesting to note that ERK inhibitors may also play a key role in sensing damage levels and reducing the immune response in other post-mitotic cells outside the ear, such as in the kidney and neurodegenerative disorders of the joints and brain [ 88 , 89 , 90 ]. Finally, ERK1/2 inhibition has been shown to affect activity-regulated cytoskeleton-associated proteins (Arc) in neurons, which could be another possible mechanism of the protection from hearing loss seen with ERK inhibition [ 91 , 92 ].…”