The effect of MEK1/2 inhibitors on cisplatin-induced acute kidney injury (AKI) and cancer growth in mice.

Abstract

In a clinically-relevant model of 4 week, low-dose cisplatin-induced AKI, mice were injected subcutaneously with non small cell lung cancer (NSCLC) cells that harbor an activating Kirsten rat sarcoma viral oncogene homolog (KRAS)G12V mutation. Phospho extracellular signal-regulated kinase1/2 (pERK1/2) expression in kidney and tumors was decreased by the MEK1/2 inhibitors, U0126 and trametinib, that potently inhibit pERK1/2. U0126 resulted in a significant improvement in kidney function, acute tubular necrosis (ATN) and tubular cell apoptosis in mice with AKI. Genes that were significantly decreased by U0126 were heat shock protein 1, cyclin-dependent kinase 4 (CDK4) and stratifin (14-3-3σ). U0126 resulted in a significant decrease in tumor weight and volume and significantly increased the chemotherapeutic effect of cisplatin. Trametinib, a MEK1/2 inhibitor that is FDA-approved for the treatment of cancer, did not result in functional protection against AKI or worse AKI, but dramatically decreased tumor growth more than cisplatin. Smaller tumors in cisplatin or MEK1/2 inhibitor-treated mice were not related to changes in microtubule-associated proteins 1A/1B light chain 3B (LC3-II), p62, cleaved caspase-3, granzyme B, or programmed death-ligand 1 (PD-L1). In summary, despite ERK inhibition by both U0126 and trametinib, only U0126 protected against AKI suggesting that the protection against AKI by U0126 was due to an off-target effect independent of ERK inhibition. The effect of U0126 to decrease AKI may be mediated by inhibition of heat shock protein 1, CDK4 or stratifin (14-3-3σ). Trametinib was more effective than cisplatin in decreasing tumor growth, but unlike cisplatin, trametinib did not cause AKI.

• Authors: Carolyn N Brown, Daniel J Atwood, Deepak Pokhrel, Kameswaran Ravichandran, Sara J Holditch, Sanskriti Saxena, Makoto Miyazaki, Raphael Nemenoff, Mary C M Weiser-Evans, Danica Galesic Ljubanovic, Melanie S Joy, Charles L Edelstein
• Journal: Cellular signalling (Cell Signal) Vol. 71 Pg. 109605 (07 2020) ISSN: 1873-3913 [Electronic] England
• PMID: 32194168 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Butadienes
• Lipocalin-2
• Neoplasm Proteins
• Nitriles
• Protein Kinase Inhibitors
• Pyridones
• Pyrimidinones
• U 0126
• Lcn2 protein, mouse
• trametinib
• Mitogen-Activated Protein Kinase Kinases
• Cisplatin

Topics

• Acute Kidney Injury (drug therapy)
• Animals
• Apoptosis (drug effects)
• Blood Urea Nitrogen
• Butadienes (pharmacology)
• Cell Proliferation (drug effects)
• Cisplatin (pharmacology, therapeutic use)
• Kidney (drug effects, injuries, pathology)
• Lipocalin-2 (metabolism)
• Lung Neoplasms (pathology)
• MAP Kinase Signaling System (drug effects)
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, metabolism)
• Neoplasm Proteins (metabolism)
• Nitriles (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Pyridones (pharmacology)
• Pyrimidinones (pharmacology)
• Tumor Burden (drug effects)