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Bai Y, Kim JY, Bisunke B, et al. Kidney toxicity of the BRAF-kinase inhibitor vemurafenib is driven by off-target ferrochelatase inhibition. Kidney Int. 2021;100(6):1214-1226doi: 10.1016/j.kint.2021.08.022.
Bai, Y., Kim, J. Y., Bisunke, B., Jayne, L. A., Silvaroli, J. A., Balzer, M. S., Gandhi, M., Huang, K. M., Sander, V., Prosek, J., Cianciolo, R. E., Baker, S. D., Sparreboom, A., Jhaveri, K. D., Susztak, K., Bajwa, A., & Pabla, N. S. (2021). Kidney toxicity of the BRAF-kinase inhibitor vemurafenib is driven by off-target ferrochelatase inhibition. Kidney international, 100(6), 1214-1226. https://doi.org/10.1016/j.kint.2021.08.022
Bai, Yuntao, et al. "Kidney toxicity of the BRAF-kinase inhibitor vemurafenib is driven by off-target ferrochelatase inhibition." Kidney international vol. 100,6 (2021): 1214-1226. doi: https://doi.org/10.1016/j.kint.2021.08.022
Bai Y, Kim JY, Bisunke B, Jayne LA, Silvaroli JA, Balzer MS, Gandhi M, Huang KM, Sander V, Prosek J, Cianciolo RE, Baker SD, Sparreboom A, Jhaveri KD, Susztak K, Bajwa A, Pabla NS. Kidney toxicity of the BRAF-kinase inhibitor vemurafenib is driven by off-target ferrochelatase inhibition. Kidney Int. 2021 Dec;100(6):1214-1226. doi: 10.1016/j.kint.2021.08.022. Epub 2021 Sep 15. PMID: 34534550; PMCID: PMC8608726.
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Kidney Int. 2021 Dec;100(6):1214-1226. doi: 10.1016/j.kint.2021.08.022. Epub 2021 Sep 15.

Kidney toxicity of the BRAF-kinase inhibitor vemurafenib is driven by off-target ferrochelatase inhibition.

Kidney international

Yuntao Bai, Ji Young Kim, Bijay Bisunke, Laura A Jayne, Josie A Silvaroli, Michael S Balzer, Megha Gandhi, Kevin M Huang, Veronika Sander, Jason Prosek, Rachel E Cianciolo, Sharyn D Baker, Alex Sparreboom, Kenar D Jhaveri, Katalin Susztak, Amandeep Bajwa, Navjot Singh Pabla

Affiliations

  1. Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
  2. Department of Genetics, Genomics, and Informatics, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, USA.
  3. Department of Medicine and Genetics, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  4. Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
  5. Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
  6. Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA.
  7. Division of Kidney Diseases and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra-Northwell, Northwell Health, Great Neck, New York, USA.
  8. Department of Genetics, Genomics, and Informatics, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, USA; Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, USA; Transplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, College of Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee, USA.
  9. Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA. Electronic address: [email protected].

PMID: 34534550 PMCID: PMC8608726 DOI: 10.1016/j.kint.2021.08.022

Abstract

A multitude of disease and therapy related factors drive the frequent development of kidney disorders in cancer patients. Along with chemotherapy, the newer targeted therapeutics can also cause kidney dysfunction through on and off-target mechanisms. Interestingly, among the small molecule inhibitors approved for the treatment of cancers that harbor BRAF-kinase activating mutations, vemurafenib can trigger tubular damage and acute kidney injury. BRAF is a proto-oncogene involved in cell growth. To investigate the underlying mechanisms, we developed cell culture and mouse models of vemurafenib kidney toxicity. At clinically relevant concentrations vemurafenib induces cell-death in transformed and primary mouse and human kidney tubular epithelial cells. In mice, two weeks of daily vemurafenib treatment causes moderate acute kidney injury with histopathological characteristics of kidney tubular epithelial cells injury. Importantly, kidney tubular epithelial cell-specific BRAF gene deletion did not influence kidney function under normal conditions or alter the severity of vemurafenib-associated kidney impairment. Instead, we found that inhibition of ferrochelatase, an enzyme involved in heme biosynthesis contributes to vemurafenib kidney toxicity. Ferrochelatase overexpression protected kidney tubular epithelial cells and conversely ferrochelatase knockdown increased the sensitivity to vemurafenib-induced kidney toxicity. Thus, our studies suggest that vemurafenib-associated kidney tubular epithelial cell dysfunction and kidney toxicity is BRAF-independent and caused, in part, by off-target ferrochelatase inhibition.

Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Keywords: BRAF kinase; acute kidney injury; ferrochelatase; onconephrology; protein kinase inhibitors; renal tubular epithelial cells

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