Kidney toxicity of the BRAF-kinase inhibitor vemurafenib is driven by off-target ferrochelatase inhibition.
BRAF kinase
acute kidney injury
ferrochelatase
onconephrology
protein kinase inhibitors
renal tubular epithelial cells
Journal
Kidney international
ISSN: 1523-1755
Titre abrégé: Kidney Int
Pays: United States
ID NLM: 0323470
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
10
01
2021
revised:
21
07
2021
accepted:
13
08
2021
pubmed:
18
9
2021
medline:
15
12
2021
entrez:
17
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34534550
pii: S0085-2538(21)00855-3
doi: 10.1016/j.kint.2021.08.022
pmc: PMC8608726
mid: NIHMS1741456
pii:
doi:
Substances chimiques
Indoles
0
Sulfonamides
0
Vemurafenib
207SMY3FQT
BRAF protein, human
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Ferrochelatase
EC 4.99.1.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1214-1226Subventions
Organisme : NCI NIH HHS
ID : P30 CA016058
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA215802
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK117183
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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