Investigation Of Cabozantinib, A Met And Vegfr2 Inhibitor, On Tumor Metabolism And Efficacy In A Colorectal Cancer Patient-Derived Tumor Explant Model

Background: Anti-angiogenic therapy is commonly used for the treatment of metastatic colorectal cancer (mCRC). Although patients derive some clinical benefit, treatment resistance inevitably occurs. Upregulation of MET in response to anti-VEGF therapy may play an essential role in treatment resistance. Based on this premise, we investigated cabozantinib, an inhibitor of kinases including MET and VEGFR2, in mCRC patient-derived tumor explant (PDTX) models. Based on initial observations of anti-tumor activity, we hypothesized that cabozantinib may alter tumor metabolism concurrent with its antitumor effects, and compared its efficacy with regorafenib in our models. Material and Methods: Ten CRC PDTX models were treated with cabozantinib (30 mg/kg daily) or regorafenib (10 mg/kg daily) and treatment responses were determined after 28 days. The tumor growth inhibition index (TGII) was calculated to compare treatment effects on tumor growth between cabozantinib and regorafenib. RNA Seq was used to assess gene expression and pathways modulated by cabozantinib treatment. Proteins involved in metabolism and autophagy were evaluated by immunoblotting at day 3, 7 and 28. The effects of cabozantinib on tumor glucose metabolism were investigated by 18FDG-PET at baseline, 7 and 28 days following treatment. Lastly, combination effects of cabozantinib and an ULK1 inhibitor, an autophagy inhibitor, were evaluated on the HCT116 cell line by a clonogenic assay. Results: Cabozantinib (average TGII: 3.202) demonstrated antitumor effects among all 10 CRC explants that compared favorably to regorafenib (average TGII: 48.48). In addition, cabozantinib significantly reduced glucose uptake measured by 18FDG-PET at days 7 and 28. A comprehensive pathway analysis using RNA Seq post-cabozantinib treatment revealed a significant reduction in pyruvate metabolism and the TCA cycle in the most sensitive tumors. Protein analyses showed downregulation of hexokinase 1 and pyruvate dehydrogenase and a marked increase in many components of oxidative phosphorylation and autophagy (LC3 and Beclin) at day 7 and 28 following cabozantinib treatment. The combination of an ULK1 inhibitor and cabozantinib enhanced the activity of cabozantinib in the HCT116 CRC cell line. Conclusions: Cabozantinib showed significant antitumor activity compared to regorafenib in our CRC PDTX models. Alterations in glucose metabolism and autophagy were identified in cabozantinib sensitive tumors, suggesting that a shift in cellular metabolism facilitates the survival of tumor cells following treatment. The combination effect of cabozantinib and an ULK1 inhibitor supports the hypothesis that induction of autophagy may be a mechanism of cabozantinib resistance. These findings support further evaluation of cabozantinib in patients with mCRC. Acknowledgements: Exelixis for providing cabozantinib. Citation Format: Aaron J. Scott, Rachel Yahn, Stacey Bagby, Kendra Huber, Natalie Serkova, Wells Messersmith, John Arcaroli. Investigation of cabozantinib, a MET and VEGFR2 inhibitor, on tumor metabolism and efficacy in a colorectal cancer patient-derived tumor explant model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1019.