Potent antitumor activity of Cabozantinib, a c-MET and VEGFR2 Inhibitor, in a Colorectal Cancer Patient-derived Tumor Explant Model

Anti-angiogenic therapy is commonly used for the treatment of 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 anti-angiogenic therapy. MET is upregulated in response to VEGF 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 PDTX 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. Overall design: CRC PDTX Model treated with cabozantinib

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Song EK, Tai WM, Messersmith WA, Bagby S, Purkey A, Quackenbush KS, Pitts TM, Wang G, Blatchford P, Yahn R, Kaplan J, Tan AC, Atreya CE, Eckhardt G, Kelley RK, Venook A, Kwak EL, Ryan D, Arcaroli JJ