Cited by 162Colorectal Cancer Treatments and StudiesCancer Mechanisms and TherapyProtein Kinase Regulation and GTPase Signaling

Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress

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Kopetz, Scott, Lesslie, Donald P., Dallas, Nikolas A., Park, Serk I., Johnson, Marjorie, Parikh, Nila U., Kim, Michael P., Abbruzzese, James L. +3 more·2009·Cancer Research

Published version of a preprint

Abstract

Chemotherapeutic regimens for the treatment of colorectal cancer generally include oxaliplatin, although inherent and acquired resistance is common. One potential mediator of oxaliplatin sensitivity is the nonreceptor protein tyrosine kinase, Src, the activity of which correlates with disease stage and patient survival. Therefore, we investigated the effects of Src inhibition using the tyrosine kinase inhibitor dasatinib on oxaliplatin sensitivity. We show that oxaliplatin acutely activates Src and that combination treatment with dasatinib is synergistic in a cell-line dependent manner, with the level of Src activation correlating with extent of synergy in a panel of six cell lines. Intracellular reactive oxygen species (ROS) are generated after oxaliplatin treatment, and ROS potently activates Src. Pretreatment with antioxidants inhibits oxaliplatin-induced Src activation. In oxaliplatin-resistant cell lines, Src activity is constitutively increased. In a mouse model of colorectal liver metastases, treatment with oxaliplatin also results in chronic Src activation. The combination of dasatinib and oxaliplatin results in significantly smaller tumors compared with single-agent treatment, corresponding with reduced proliferation and angiogenesis. Therefore, we conclude that oxaliplatin activates Src through a ROS-dependent mechanism. Src inhibition increases oxaliplatin activity both in vitro and in vivo. These results suggest that Src inhibitors combined with oxaliplatin may have efficacy in metastatic colon cancer and may provide the first indication of a molecular phenotype that might be susceptible to such combinations. [Cancer Res 2009;69(9):3842–9]

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Crossref · 10.1158/0008-5472.can-08-2246

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Research works printed but not linked: 2

  1. [46]Eng C Kopetz S Morris J Phase II Study of the Novel Oral Src-Kinase Inhibitor, AZD0530, in Previously Treated Advanced Colorectal Cancer Patients 2008 Proceedings of the 98th Annual Meeting of the American Association for Cancer Research; 2008 San Diego, CA AACR; 2008. p. LB-76
  2. [47]Kopetz S Wolff RACE Phase IB study of Src inhibition with dasatinib in combination with 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) and cetuximab in metastatic colorectal cancer 2008 Proceedings of the 98th Annual Meeting of the American Association for Cancer Research; 2008 April 12–16, 2008 San Diego, CA AACR; 2008. p. LB-69

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Authors
Kopetz, S., Lesslie, D. P., Dallas, N. A., Park, S. I., Johnson, M., Parikh, N. U., Kim, M. P., Abbruzzese, J. L., Ellis, L. M., Chandra, J., & Gallick, G. E.
Affiliations
  • 1Cancer Biology, Departments of
  • 2Gastrointestinal Medical Oncology,
  • The University of Texas MD Anderson Cancer Center (US)
Venue
Cancer Research
Published
2009-04-30
Volume
69
Issue
9
Pages
3842-3849
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
OpenAlex
W2092343827
Cited by
160
References
46
Citations by year
2026: 2 · 2025: 4 · 2024: 6 · 2023: 9 · 2022: 9 · 2021: 7 · 2020: 7 · 2019: 4 · 2018: 6 · 2017: 7 · 2016: 11 · 2015: 9 · 2014: 8 · 2013: 12 · 2012: 16
FWCI
9.84
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5p20ca101936-05, KL2TR000370, CA088084, CA101936)
  • National Cancer Institute (U54CA090810, K23CA136980, T-32 CA 09599, P20-CA101936, L30 CA124227, T32CA009599, K12CA088084)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
dasatinib, oxaliplatin, Src family kinases, colorectal cancer, combination chemotherapy, oxidative stress, reactive oxygen species, drug synergy, chemoresistance, antioxidants, colorectal liver metastases, angiogenesis, cell proliferation
MeSH terms
Dasatinib, Oxaliplatin, Animals, Antineoplastic Combined Chemotherapy Protocols, Colonic Neoplasms, Drug Synergism, Humans, Liver Neoplasms, Experimental, Male, Mice, Nude, Neovascularization, Pathologic, Organoplatinum Compounds, Pyrimidines, Random Allocation, Thiazoles, Down-Regulation, Apoptosis, Reactive Oxygen Species, Oxidative Stress, src-Family Kinases, HT29 Cells, Vascular Endothelial Growth Factor A, HCT116 Cells, Protein Kinase Inhibitors, Cell Growth Processes, Mice

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