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CBP/catenin antagonist safely eliminates drug-resistant leukemia-initiating cells

Oncogene volume 35, pages 3705–3717 (2016)Cite this article

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Abstract

CREB-binding protein (CBP) and p300 are highly homologous transcriptional coactivators with unique, non-redundant roles that bind a wide array of proteins, including catenins—β and γ. ICG-001 is a small-molecule inhibitor that specifically inhibits the CBP/catenin interaction. Importantly, ICG-001 does not inhibit the p300/catenin interaction. We demonstrate that specifically inhibiting the interaction between CBP and catenin with ICG-001 results in the differentiation of quiescent drug-resistant chronic myelogenous leukemia-initiating cells (CML LICs), thereby sensitizing them to BCR-ABL tyrosine kinase inhibitors, for example, Imatinib. Using ICG-001 in a NOD/SCID/IL2Rγ−/− mouse model of engrafted human chronic myelogenous leukemia, we now demonstrate the complete elimination of engrafted leukemia after only one course of combined chemotherapy. Combination-treated animals live as long as their non-engrafted littermates. Results from these studies demonstrate that specifically antagonizing the CBP/catenin interaction with ICG-001 can eliminate drug-resistant CML LICs without deleterious effects to the normal endogenous hematopoietic stem cell population.

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Acknowledgements

Support from USC Norris Comprehensive Cancer Center Support Grant P30 CA014089, NIH 1R01CA166161-01A1 and NIH 1R01 HL112638-01 is gratefully acknowledged.

Author contributions

YZ: conception, design, experimentation, data analyses and interpretation, writing, and final approval of the manuscript; DM, MM, CN, YW, EM, GS, AK and YH: experimentation; J-LT: writing; and MK: conception, design, data analysis and interpretation, writing, financial support, and final approval of the manuscript.

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Authors and Affiliations

  1. Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Y Zhao

  2. Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Y Zhao, M McMillian, C Nguyen, E Melendez, G Smbatyan, J-L Teo & M Kahn

  3. Center for Molecular Pathways and Drug Discovery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Y Zhao, D Masiello, M McMillian, C Nguyen, Y Wu, E Melendez, G Smbatyan, A Kida, Y He, J-L Teo & M Kahn

  4. Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    M Kahn

  5. Department of Molecular Pharmacology and Toxicology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    M Kahn

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  1. Y Zhao
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Correspondence to M Kahn.

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Competing interests

JLT is an equity holder in Prism Pharma Co. Ltd. The other authors declare no conflict of interest.

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Zhao, Y., Masiello, D., McMillian, M. et al. CBP/catenin antagonist safely eliminates drug-resistant leukemia-initiating cells. Oncogene 35, 3705–3717 (2016). https://doi.org/10.1038/onc.2015.438

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  • DOI: https://doi.org/10.1038/onc.2015.438

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