Cabozantinib-induced edema in zebrafish represents an adverse effect characterized by defects in lymphatic...

Tyrosine kinase inhibitors (TKIs) are a major class of targeted cancer therapy drugs. Overcoming the limitations of approved TKIs and the development of new TKIs continues to be an important need. The adoption of higher throughput and accessible animal models to evaluate TKI adverse effects will help in this regard. We exposed zebrafish larvae to a set of 22 Food and Drug Administration-approved TKIs and assessed mortality, early developmental abnormalities, and gross morphological abnormalities posthatching. We found edema posthatching as a consistent and prominent consequence of VEGFR inhibitors, and of cabozantinib in particular. The edema occurred at concentrations that did not cause lethality or any other abnormality, and was independent of the developmental stage. Further experiments identified loss of blood and lymphatic vasculature, and suppression of renal function in larvae exposed to 10 µM cabozantinib. Molecular analysis showed downregulation of the vasculature marker genes vegfr, prox1a, sox18, and the renal function markers nephrin and podocin as the potential molecular basis for the above defects, implicating them in the mechanism of cabozantinib-induced edema. Our findings reveal edema as a previously unreported phenotypic effect of cabozantinib and identify the likely mechanistic basis. These findings also highlight the need for studies investigating edema due to vascular and renal dysfunction as a potential clinical adverse effect of cabozantinib, and possibly other VEGFR inhibitors.