off-target ferrochelatase inhibition.
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.
For full article: https://pubmed.ncbi.nlm.nih.gov/34534550/
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.
Keywords: BRAF kinase; acute kidney injury; ferrochelatase; onconephrology; protein kinase inhibitors; renal tubular epithelial cells.