Abstract
The Hippo pathway plays an important role in the growth, development, and regeneration of cells and organs. Its effector molecules, including the transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator PDZ-binding motif (TAZ), work with the transcription factor transcriptional enhanced associate domain (TEAD), and they are involved in carcinogenesis, such as malignant pleural mesothelioma (MPM). Thus, TEAD inhibitors are expected to have potent anticancer activity against MPM. However, YAP or TAZ conditional knockout mice show abnormal findings in various tissues, indicating toxicity concerns for the Hippo pathway inhibitors. In the present study, we evaluated the systemic toxicity of K-975, a novel TEAD inhibitor, in rats. Oral administration of K-975 for 1 week induced nephrotoxicity, including proteinuria with glomerular podocyte effacement, but it completely recovered after a 2-week recovery period. Urinalysis suggested that the urinary albumin index (urinary albumin/urinary creatinine) was the most sensitive marker for detecting K-975-induced nephrotoxicity. After 3 cycles of 1-week administration followed by a 2-week recovery period, nephrotoxicity was reversible; however, incomplete reversibility was observed in some rats with severe proteinuria. In conclusion, our study revealed that oral K-975 treatment in rats induced severe proteinuria with podocyte foot process effacement, but it was reversible and monitorable by the urinary albumin index. These results provide important information for developing K-975 as an anticancer drug.
