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Potent antitumor activity of cabozantinib, a c‐ MET and VEGFR 2 inhibitor, in a colorectal cancer patient‐derived tumor explant model
Author(s) -
Song EunKee,
Tai WM,
Messersmith Wells A.,
Bagby Stacey,
Purkey Alicia,
Quackenbush Kevin S.,
Pitts Todd M.,
Wang Guoliang,
Blatchford Patrick,
Yahn Rachel,
Kaplan Jeffrey,
Tan Aik Choon,
Atreya Chloe E.,
Eckhardt Gail,
Kelley Robin K.,
Venook Alan,
Kwak Eunice L.,
Ryan David,
Arcaroli John J.
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29225
Subject(s) - cabozantinib , cancer research , colorectal cancer , medicine , angiogenesis , cancer , pi3k/akt/mtor pathway , downregulation and upregulation , carcinogenesis , biology , signal transduction , vegf receptors , gene , biochemistry
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.