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Sensitivity and Resistance to Therapy

Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and γ-irradiation

Leukemia volume 15, pages 1232–1239 (2001)Cite this article

Abstract

Integrin-mediated cellular adhesion to extracellular matrix (ECM) components is an important determinant of chemotherapeutic response of human myeloma cells. Here, we demonstrate that when K562 chronic myelogenous leukemia (CML) cells are adhered to fibronectin (FN), they become resistant to apoptosis induced by the BCR/ABL inhibitors AG957 and STI-571, as well as DNA damaging agents and γ-irradiation. This phenomenon, termed cell adhesion-mediated drug resistance (CAM-DR), was induced by adhesion through the α5β1 (VLA-5) integrin. Phosphotyrosine analysis demonstrates that anti-apoptotic signaling through integrins in K562 cells is independent of the tyrosine kinases activated by BCR/ABL, with the possible exception of an unknown 80 kDa protein. Cytoprotection of FN-adhered CML cells indicates that tumor–ECM interactions may be critical for the emergence of drug-resistant tumor populations and treatment failure in this disease. Antagonists of β1 integrin-mediated adhesion or corresponding signal transduction elements may sensitize CML cells to chemotherapy and prevent resistance to the novel BCR/ABL kinase inhibitors being used for the treatment of this disease.

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Acknowledgements

We would like to acknowledge the Flow Cytometry Core facility at the H Lee Moffitt Cancer Center. We would also like to thank Marc Oshiro for assisting with the RNase protection assays, Lindsey Todd for performing Western blotting for the Bcl-2 family proteins and Lee Wisner for help with apoptosis assays. This work was supported in part by CA77859 and CA82533.

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  1. Department of Interdisciplinary Oncology and Clinical Investigations Program, and H Lee Moffitt Cancer Center and Research Institute, University of South Florida Tampa FL, USA

    JS Damiano, LA Hazlehurst & WS Dalton

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Damiano, J., Hazlehurst, L. & Dalton, W. Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and γ-irradiation. Leukemia 15, 1232–1239 (2001). https://doi.org/10.1038/sj.leu.2402179

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