BRAF/MEK inhibitor-associated nephrotoxicity in a real-world setting and human kidney cells
| Autor: | Tomoya Kataoka, Akimasa Sanagawa, Kazunori Kimura, Nanaka Mori, Natsumi Tomita, Yuji Hotta, Masahiro Tohkin |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Proto-Oncogene Proteins B-raf
Cancer Research Cell Survival Pyridones Antineoplastic Agents Pyrimidinones Nephrotoxicity Cell Line chemistry.chemical_compound Piperidines Oximes medicine Humans Pharmacology (medical) Vemurafenib Pharmacology Cobimetinib Trametinib Mitogen-Activated Protein Kinase Kinases Cell Death Dose-Response Relationship Drug business.industry MEK inhibitor Melanoma Acute kidney injury Imidazoles Dabrafenib Acute Kidney Injury medicine.disease Oncology chemistry Cancer research Azetidines business medicine.drug |
| Zdroj: | Anti-cancer drugs. 32(10) |
| ISSN: | 1473-5741 |
| Popis: | Acute kidney injury (AKI) associated with cancer chemotherapy can be life-threatening. Inhibitors of rapidly accelerated fibrosarcoma kinase B (BRAF)-mutants and mitogen-activated extracellular signal-regulated kinase (MEK) administered as combination therapy are effective against BRAF-mutant melanoma, but drug-associated AKI events were reported after marketing. Here, we examined the nephrotoxicity of two BRAF inhibitors, vemurafenib and dabrafenib, and two MEK inhibitors, cobimetinib and trametinib, in a real-world setting and human kidney cells. Target drug-associated AKI signals were detected by reporting odds ratio (ROR) derived from report data in the Food and Drug Administration Adverse Events Reporting System database. In-vitro cytotoxicity was evaluated in proximal renal tubular epithelial cells (RPTEC), glomerular endothelial cells (GEnC), and glomerular epithelial cells (GEpC). Results AKI RORs associated with vemurafenib [ROR, 3.28; confidence interval (CI), 2.91-3.69] and cobimetinib (ROR, 4.40; CI, 3.55-5.45) were higher than those associated with dabrafenib (ROR, 1.35; CI, 1.15-1.60) and trametinib (ROR, 1.32; CI, 1.11-1.56). Vemurafenib reduced cell viability and increased cell death in RPTEC and GEpC at 10 μM, which was below the mean maximum concentration in blood under steady-state condition [115.7 μM (56.7 μg/mL)]. No vemurafenib-associated cytotoxicity was detected in GEnC. Mean maximum concentrations of cobimetinib, dabrafenib and trametinib did not induce cell death. Conclusion This work revealed that vemurafenib had stronger cytotoxic effects on tubular and glomerular epithelial cells than the other BRAF and MEK inhibitors. Hence, we recommend careful monitoring for clinical signs of kidney injury in patients treated with vemurafenib. |
| Databáze: | OpenAIRE |
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