In vitro evaluation of autophagic effects of cabozantinib in renal cancer cell lines

Autophagy is a mechanism that involves the recycling of damaged intracellular components by lysosomes against stress and may act as a cell protective mechanism or a process leading to cell death by playing a dual role in many cancers. Although many different anti-cancer drugs are used in the treatment of renal cell carcinoma (RCC), the five-year survival rate is 10% due to drug resistance after treatment, and autophagy is thought to be largely responsible for this resistance. Cabozantinib is a multiple tyrosine kinase inhibitor approved by the FDA in 2016 for the treatment of RCC and is known to significantly increase the survival rate compared to other anti-cancer drugs used in RCC. In this thesis, the autophagic and apoptotic activity of cabozantinib in A498 and ACHN cell lines were demonstrated. In both cell lines, cabozantinib activated autophagy by causing accumulation of LC3-II and ULK1 and inhibition of autophagy with chloroquine (CQ) increased apoptosis. Cabozantinib caused mitochondrial hyperpolarization in both cell lines, possibly resulting from the accumulation of cabozantinib in mitochondria and causing autophagic activation via AMPK and increased the amount of ROS in the cell. Cabozantinib, a Met inhibitor, suppressed Akt, one of the proteins downstream of Met and known to be associated with autophagy, but failed to potently suppress ERK. Cabozantinib has been shown to arrest cells in S or G2/M phase. This suggests that cabozantinib directly or indirectly affects DNA damage. In conclusion, the information obtained from this thesis study shows that regulation of autophagy will provide new approaches in the treatment of RCC.