Potent antitumor activity of cabozantinib,a c‐MET and VEGFR2 inhibitor,in a colorectal cancer patient‐derived tumor explant model |
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Authors: | Eun‐Kee Song WM Tai Wells A Messersmith Stacey Bagby Alicia Purkey Kevin S Quackenbush Todd M Pitts Guoliang Wang Patrick Blatchford Rachel Yahn Jeffrey Kaplan Aik Choon Tan Chloe E Atreya Gail Eckhardt Alan Venook Eunice L Kwak David Ryan John J Arcaroli |
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Institution: | 1. Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Aurora, CO;2. Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea;3. University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA;4. Massachusetts General Hospital and Harvard Medical School, Boston, MA |
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Abstract: | Antiangiogenic therapy is commonly used for the treatment of colorectal cancer (CRC). Although patients derive some clinical benefit, treatment resistance inevitably occurs. The MET signaling pathway has been proposed to be a major contributor of resistance to antiangiogenic therapy. MET is upregulated in response to vascular endothelial growth factor pathway inhibition and plays an essential role in tumorigenesis and progression of tumors. In this study, we set out to determine the efficacy of cabozantinib in a preclinical CRC patient‐derived tumor xenograft model. We demonstrate potent inhibitory effects on tumor growth in 80% of tumors treated. The greatest antitumor effects were observed in tumors that possess a mutation in the PIK3CA gene. The underlying antitumor mechanisms of cabozantinib consisted of inhibition of angiogenesis and Akt activation and significantly decreased expression of genes involved in the PI3K pathway. These findings support further evaluation of cabozantinib in patients with CRC. PIK3CA mutation as a predictive biomarker of sensitivity is intriguing and warrants further elucidation. A clinical trial of cabozantinib in refractory metastatic CRC is being activated. |
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Keywords: | colorectal cancer angiogenesis c‐MET RET VEGFR2 PIK3CA |
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