Potent antitumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal cancer patient-derived tumor explant model

Eun Kee Song, W. M. 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, Robin K. Kelley, Alan Venook, Eunice L. Kwak, David Ryan, John J. Arcaroli

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

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. What's new? Members of the MET and vascular endothelial growth factor (VEGF) signaling pathways are important targets in anticancer drug development, owing to their association with tumor progression and metastasis. Of particular interest in tumor progression is MET upregulation in response to VEGF pathway inhibition. Here, cabozantinib, a VEGFR2 and MET inhibitor, was found to exert potent antitumor activity in a preclinical colorectal cancer patient-derived tumor xenograft model. Tumors possessing a PIK3CA mutation were highly sensitive to cabozantinib. The results suggest that cabozantinib may be of value in the treatment of colorectal cancer, with PIK3CA mutation capable of predicting therapeutic sensitivity.

Original languageEnglish
Pages (from-to)1967-1975
Number of pages9
JournalInternational Journal of Cancer
Volume136
Issue number8
DOIs
Publication statusPublished - 2015 Apr 15

Keywords

  • Angiogenesis
  • C-MET
  • Colorectal cancer
  • PIK3CA
  • RET
  • VEGFR2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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