Abstract: FR-OR01
Role of Off-Target Ferrochelatase Inhibition in Vemurafenib Nephrotoxicity
Session Information
- AKI: Novel Mechanisms and Targets of Injury
November 05, 2021 | Location: Simulive, Virtual Only
Abstract Time: 04:30 PM - 06:00 PM
Category: Onco-Nephrology
- 1500 Onco-Nephrology
Authors
- Silvaroli, Josie A., The Ohio State University, Columbus, Ohio, United States
- Kim, Ji Young, The Ohio State University, Columbus, Ohio, United States
- Pabla, Navjot Singh P., The Ohio State University, Columbus, Ohio, United States
Background
Complications linked with both cancer and anti-cancer therapeutics can trigger kidney injury. For targeted anti-cancer therapeutics, nephrotoxicity may occur because of on- or off- target mechanisms. In melanoma and other cancers with BRAF kinase activating mutations, targeted small molecule therapeutics such as vemurafenib, and dabrafenib have shown remarkable clinical benefits. However, recent clinical studies have shown that a significant number of patients that receive vemurafenib develop AKI through mechanisms that remain unknown. Here we have developed cell culture and murine models of vemurafenib nephrotoxicity to understand the causal mechanisms.
Methods
We established a murine model of vemurafenib toxicity through oral administration of 20 mg/kg vemurafenib in C57B6/J mice. We confirmed kidney damage and toxicity in these mice through measurement of blood urea nitrogen, serum creatinine, histological analysis, and TUNEL staining. Using the GGT-Cre strain we have also generated BRAF conditional knockout mice. To understand the role of ferrochelatase we used a hydrodynamic siRNA injection approach or heterozygous (+/fch) mutant mice. Control and gene knockout mice were treated with vemurafenib to examine the role of BRAF and FECH in vemurafenib nephrotoxicity.
Results
We found that BRAF gene deletion in tubular epithelial cells had no influence on vemurafenib-associated AKI. Instead, we found that inhibition of ferrochelatase (FECH), an enzyme involved in heme biosynthesis contributes to vemurafenib nephrotoxicity. FECH overexpression mitigated and conversely FECH knockdown increased the sensitivity to vemurafenib nephrotoxicity.
Conclusion
In the present study, we demonstrate that the mechanism for vemurafenib nephrotoxicity is not through the BRAF kinase inhibition, but instead occurs through off-target inhibition of FECH. Furthermore, these findings suggest that along with vemurafenib, other drugs that inhibit FECH activity might cause nephrotoxicity. Together, the present study describes the development of novel experimental models of vemurafenib nephrotoxicity and reveals the underlying off-target mechanisms that contribute to renal injury.
Funding
- Other NIH Support