PT  - JOURNAL ARTICLE
AU  - Yuntao Bai
AU  - Ji Young Kim
AU  - Laura A. Jayne
AU  - Megha Gandhi
AU  - Kevin M. Huang
AU  - Josie A. Silvaroli
AU  - Veronika Sander
AU  - Jason Prosek
AU  - Kenar D. Jhaveri
AU  - Sharyn D. Baker
AU  - Alex Sparreboom
AU  - Amandeep Bajwa
AU  - Navjot Singh Pabla
TI  - Nephrotoxicity of the BRAF-kinase inhibitor Vemurafenib is driven by off-target Ferrochelatase inhibition
AID  - 10.1101/2021.01.29.428783
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.29.428783
4099  - http://biorxiv.org/content/early/2021/01/31/2021.01.29.428783.short
4100  - http://biorxiv.org/content/early/2021/01/31/2021.01.29.428783.full
AB  - A multitude of disease and therapy related factors drive the frequent development of renal disorders in cancer patients. Along with chemotherapy, the newer targeted therapeutics can also cause renal 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 (AKI). To investigate the underlying mechanisms, here, we have developed cell culture and mouse models of vemurafenib nephrotoxicity. Our studies show that at clinically relevant concentrations vemurafenib induces cell-death in transformed and primary murine and human renal tubular epithelial cells (RTEC). In mice, two weeks of daily vemurafenib treatment causes moderate AKI with histopathological characteristics of RTEC injury. Importantly, RTEC-specific BRAF gene deletion did not influence renal function under normal conditions or alter the severity of vemurafenib-associated renal impairment. Instead, we found that inhibition of ferrochelatase (FECH), an enzyme involved in heme biosynthesis contributes to vemurafenib nephrotoxicity. FECH overexpression protected RTECs and conversely FECH knockdown increased the sensitivity to vemurafenib nephrotoxicity. Collectively, these studies suggest that vemurafenib-associated RTEC dysfunction and nephrotoxicity is BRAF-independent and caused in part by off-target FECH inhibition.Translational Statement BRAF is the most frequently mutated protein kinase and a critical oncogenic driver in human cancers. In melanoma and other cancers with BRAF activating mutations, BRAF 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. 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.Competing Interest StatementThe authors have declared no competing interest.