title: Potent antitumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal cancer patient-derived tumor explant model.
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.
authors.affiliation: Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Aurora, CO; Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Eun-Kee
authors.initials: EK
authors.lastname: Song
authors.forename: W M
authors.initials: WM
authors.lastname: Tai
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Stacey
authors.initials: S
authors.lastname: Bagby
authors.forename: Alicia
authors.initials: A
authors.lastname: Purkey
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Quackenbush
authors.forename: Todd M
authors.initials: TM
authors.lastname: Pitts
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.forename: Patrick
authors.initials: P
authors.lastname: Blatchford
authors.forename: Rachel
authors.initials: R
authors.lastname: Yahn
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kaplan
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.forename: Chloe E
authors.initials: CE
authors.lastname: Atreya
authors.forename: Gail
authors.initials: G
authors.lastname: Eckhardt
authors.forename: Robin K
authors.initials: RK
authors.lastname: Kelley
authors.forename: Alan
authors.initials: A
authors.lastname: Venook
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
authors.forename: David
authors.initials: D
authors.lastname: Ryan
authors.forename: John J
authors.initials: JJ
authors.lastname: Arcaroli
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D020533:Angiogenesis Inhibitors; D000813:Anilides; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011725:Pyridines; C558660:cabozantinib; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt
keywords: PIK3CA; RET; VEGFR2; angiogenesis; c-MET; colorectal cancer