Cabozantinib Exhibits Potent Antitumor Activity in Colorectal Cancer Patient-Derived Tumor Xenograft Models via Autophagy and Signaling Mechanisms

Molecular Cancer Therapeutics
Aaron J ScottWells A Messersmith

Abstract

Antiangiogenic 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 (RTK) 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 30 mg/kg daily versus regorafenib 10 mg/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 with regorafenib (average TGII 3.202 vs. 48.48, respectively; P = 0.007). Cabozantinib significantly reduced vascularity and glucose uptake compared with baseline. Gene pathway analysis showed that cab...Continue Reading

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Citations

Sep 16, 2020·Cancer Metastasis Reviews·Michael W LeeAnna Capasso
Jul 30, 2019·Small Methods·Weijun WeiWeibo Cai
Oct 23, 2019·Cancers·Marta Pérez-HernándezVanessa Soto-Cerrato
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Dec 3, 2020·Cancer Research·Natalie J SerkovaRalph P Mason
Apr 17, 2020·Signal Transduction and Targeted Therapy·Yuan-Hong XieJing-Yuan Fang
Mar 25, 2021·Cancer Management and Research·Zhitao LiBingqing Hui
Sep 3, 2021·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Tsuyoshi OsakaTakahito Hara
Jun 3, 2021·Current Cancer Drug Targets·Negin Chaeichi-TehraniAmir Avan

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