Cabozantinib exhibits potent antitumor activity in colorectal cancer patient-derived tumor xenograft models via autophagy and signaling mechanisms

Anti-angiogenic therapy used in treatment of metastatic colorectal cancer (mCRC) inevitably succumbs to treatment resistance. Upregulation of MET may play an essential role to acquired anti-VEGF resistance. We previously reported that cabozantinib (XL184), an inhibitor of receptor tyrosine kinases (RTKs) including MET, AXL, and VEGFR2, had potent antitumor effects in mCRC patient-derived tumor explant models. In this study, we examined the mechanisms of cabozantinib sensitivity, using regorafenib as a control. The tumor growth inhibition index (TGII) was used to compare treatment effects of cabozantinib 30mg/kg daily versus regorafenib 10mg/kg daily for a maximum of 28 days in 10 PDX mouse models. In vivo angiogenesis and glucose uptake were assessed using dynamic contrast-enhanced (DCE)-MRI and [18F]-FDG-PET imaging, respectively. RNA Seq, RTK assay, and immunoblotting analysis were used to evaluate gene pathway regulation in vivo and in vitro. Analysis of TGII demonstrated significant antitumor effects with cabozantinib compared to regorafenib (average TGII 3.202 versus 48.48, respectively; P = 0.007). Cabozantinib significantly reduced vascularity and glucose uptake compared to baseline. Gene pathway analysis showed that cabozantinib significantly decreased protein activity involved in glycolysis and upregulated proteins involved in autophagy compared to control, whereas regorafenib did not. The combination of two separate anti-autophagy agents, SBI-0206965 and chloroquine, plus cabozantinib increased apoptosis in vitro. Cabozantinib demonstrated significant antitumor activity, reduction in tumor vascularity, increased autophagy, and altered cell metabolism compared to regorafenib. Our findings support further evaluation of cabozantinib and combinational approaches targeting autophagy in CRC.