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

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

doi:10.1016/j.kint.2021.08.022

Cited by 18 publications

(18 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…41 However, recent data suggest that the renal changes are not pharmacologically mediated and instead are off-target effects related to the inhibition of ferrochelatase. 42 Other BRaf inhibitors show no similar adverse effects in kidney and were not nephrotoxic in patients, further indicating this renal effect is unrelated to pharmacologic inhibition of BRaf pathways. While vemurafenib administration resulted in moderate AKI and tubular degeneration in mice after only 14 days, BRaf inhibitors other than vemurafenib have not been associated with significant kidney effects in nonclinical studies.…”

Section: Targeted Therapies With Small Molecules and Monoclonal Antib...mentioning

confidence: 92%

“…40 In a study of 17 renal biopsies from patients taking bevacizumab that had suspected drug-related renal compromise, all had evidence of microangiopathy with pseudothrombi and multiple patients were diagnosed with nephrotic syndrome. 40,42 Glomerular effects, including proteinuria, have been noted in nonclinical studies with VEGF inhibitors, with more pronounced changes including glomerular dysmorphogenesis noted in juvenile toxicity studies in rodents. 2 Bevacizumab administration to rats results in damage to podocytes and associated membrane proteins and this is thought to be the mechanism across species.…”

Section: Targeted Therapies With Small Molecules and Monoclonal Antib...mentioning

confidence: 99%

“…While vemurafenib administration resulted in moderate AKI and tubular degeneration in mice after only 14 days, BRaf inhibitors other than vemurafenib have not been associated with significant kidney effects in nonclinical studies. 42 Dabrafenib resulted in distal tubule toxicity in juvenile rodents, but the finding has been shown to be species and age specific and does not translate to patients. 45…”

Section: Targeted Therapies With Small Molecules and Monoclonal Antib...mentioning

confidence: 99%

See 2 more Smart Citations

Kidney Effects by Alternative Classes of Medicines in Patients and Relationship to Effects in Nonclinical Toxicity Studies

Frazier¹

2022

Toxicol Pathol

View full text Add to dashboard Cite

Drug-induced kidney injury has historically been associated with renal tubule injury related to small molecule pharmaceuticals such as nonsteroidal anti-inflammatory drugs, antineoplastic agents, or antibiotics, but as a greater number of alternative classes of medicines such as biotherapeutics, molecular-targeted antineoplastic drugs, chimeric antigen receptor T-cell therapies, antibody-drug conjugates, oligonucleotide therapies, or other immunomodulatory drugs come to market, the presentation of drug-induced nephrotoxicity is changing. This review article describes the potential rare clinical events in drug-induced kidney injury that might be noted with these new therapies and their potential impact on patients. Potential pathogenic mechanisms related to immunogenicity, immune complex formation, and stimulation of downstream proinflammatory pathways with some of these alternative medicine classes have resulted in the potential for glomerulonephritis, acute interstitial nephritis, renal vasculitis, and other immune-mediated renal disorders in humans. This contrasts with nonclinical toxicity studies, where biologic therapies more often result in vasculitis and glomerulonephritis associated with antidrug antibodies and immunomodulatory pharmacology, and which are not always predictive of clinical effects. While nonclinical antidrug antibody-related renal disease is generally not clinically relevant, other immune-mediated nephrotoxicities associated with immunomodulatory drugs may be predictive of clinical adverse events. Fortunately, these conditions are still rare and account for a small percentage of serious adverse events in kidneys of patients.

show abstract

Section: Targeted Therapies With Small Molecules and Monoclonal Antib...mentioning

confidence: 92%

Section: Targeted Therapies With Small Molecules and Monoclonal Antib...mentioning

confidence: 99%

Section: Targeted Therapies With Small Molecules and Monoclonal Antib...mentioning

confidence: 99%

See 1 more Smart Citation

Kidney Effects by Alternative Classes of Medicines in Patients and Relationship to Effects in Nonclinical Toxicity Studies

Frazier¹

2022

Toxicol Pathol

View full text Add to dashboard Cite

show abstract

“…Beyond the phototoxicity effect of off-target ferrochelatase inhibition by these chemotherapies, cellular heme depletion could also be a concern. Recently, nephrotoxicity of B-RAF-kinase inhibitor, Vemurafenib, in patients with metastatic melanoma has been attributed to ferrochelatase inhibition ( Bai et al, 2021 ) ( Figure 6 ). Of note is that Dabrafenib, a B-RAF inhibitor that does not inhibit ferrochelatase ( Klaeger et al, 2016 ), has less renal toxicity than Vemurafenib ( Jhaveri et al, 2015 ).…”

Section: Regulation Of Ferrochelatase Activitymentioning

confidence: 99%

“…The renal toxicity of Vemurafenib is independent of light exposure, hence, not triggered by protoporphyrin IX accumulation. Studies suggest that it could be as a result of heme depletion instead, since knockdown of ferrochelatase accelerates the Vemurafenib-induced nephrotoxicity while ferrochelatase overexpression compensates for it ( Bai et al, 2021 ). Thus, kinase inhibitors with off-target ferrochelatase inhibition might pose a risk of inducing mitochondrial dysfunction.…”

Section: Regulation Of Ferrochelatase Activitymentioning

confidence: 99%

Ferrochelatase: Mapping the Intersection of Iron and Porphyrin Metabolism in the Mitochondria

David

Bhuiyan

Dailey

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Porphyrin and iron are ubiquitous and essential for sustaining life in virtually all living organisms. Unlike iron, which exists in many forms, porphyrin macrocycles are mostly functional as metal complexes. The iron-containing porphyrin, heme, serves as a prosthetic group in a wide array of metabolic pathways; including respiratory cytochromes, hemoglobin, cytochrome P450s, catalases, and other hemoproteins. Despite playing crucial roles in many biological processes, heme, iron, and porphyrin intermediates are potentially cytotoxic. Thus, the intersection of porphyrin and iron metabolism at heme synthesis, and intracellular trafficking of heme and its porphyrin precursors are tightly regulated processes. In this review, we discuss recent advances in understanding the physiological dynamics of eukaryotic ferrochelatase, a mitochondrially localized metalloenzyme. Ferrochelatase catalyzes the terminal step of heme biosynthesis, the insertion of ferrous iron into protoporphyrin IX to produce heme. In most eukaryotes, except plants, ferrochelatase is localized to the mitochondrial matrix, where substrates are delivered and heme is synthesized for trafficking to multiple cellular locales. Herein, we delve into the structural and functional features of ferrochelatase, as well as its metabolic regulation in the mitochondria. We discuss the regulation of ferrochelatase via post-translational modifications, transportation of substrates and product across the mitochondrial membrane, protein-protein interactions, inhibition by small-molecule inhibitors, and ferrochelatase in protozoal parasites. Overall, this review presents insight on mitochondrial heme homeostasis from the perspective of ferrochelatase.

show abstract

An overview of RAF kinases and their inhibitors (2019–2023)

Hashem,

Shahin,

Al Hindawi

et al. 2024

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

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

Cited by 18 publications

References 74 publications

Kidney Effects by Alternative Classes of Medicines in Patients and Relationship to Effects in Nonclinical Toxicity Studies

Kidney Effects by Alternative Classes of Medicines in Patients and Relationship to Effects in Nonclinical Toxicity Studies

Ferrochelatase: Mapping the Intersection of Iron and Porphyrin Metabolism in the Mitochondria

An overview of RAF kinases and their inhibitors (2019–2023)

Contact Info

Product

Resources

About