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Preferential sensitivity to HDAC inhibitors in tumors with CREBBP mutation

Cancer Gene Therapy volume 27, pages 294–300 (2020)Cite this article

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Abstract

Mutations in the gene encoding for the histone acetyltransferase (HAT) CREBBP are common driver events in multiple types of human cancer, such as small cell lung cancer (SCLC) or Sonic Hedgehog medulloblastoma (SHH MB). Therefore, therapeutic options targeting such alterations are highly desired. We used human cell lines from SCLC as well as primary mouse tumor cells and genetically engineered mouse models for SHH MB to test treatment options with histone deacetylase inhibitors (HDACi) in CREBBP wild-type and mutated tumors. In contrast to CREBBP wild-type SCLC cells, CREBBP-mutated SCLC cells showed significantly lower IC50 values after treatment with HDACi. In addition, both in vitro and in vivo, HDACi had significant effects on cell proliferation of SHH-driven tumor MB cells harboring a CREBBP-mutation as compared to CREBBP wild-type controls. These data suggest that HDACi may serve as an additional therapeutic option for patients suffering from tumors driven by CREBBP mutations.

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Acknowledgements

We are indebted to Michael Schmidt, Silvia Occhionero, Marie-Christin Burmester. and Veronika Kaltenbrunn for excellent technical support.

Funding

This work was supported by grants from the German Cancer Aid, the Wilhelm-Sander Stiftung, and the Fördergemeinschaft Kinderkrebs-Zentrum Hamburg.

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Author notes

  1. These authors contributed equally: Malte Hellwig, Daniel J. Merk

Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Malte Hellwig & Ulrich Schüller

  2. Research Institute, Children’s Cancer Center Hamburg, Hamburg, Germany

    Malte Hellwig & Ulrich Schüller

  3. Center for Neuropathology, Ludwig-Maximilians-University of Munich, Munich, Germany

    Daniel J. Merk & Ulrich Schüller

  4. Hertie Institute for Clinical Brain Research, Tübingen, Germany

    Daniel J. Merk

  5. Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany

    Beat Lutz

  6. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Ulrich Schüller

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  1. Malte Hellwig
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  4. Ulrich Schüller
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Correspondence to Ulrich Schüller.

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Hellwig, M., Merk, D.J., Lutz, B. et al. Preferential sensitivity to HDAC inhibitors in tumors with CREBBP mutation. Cancer Gene Ther 27, 294–300 (2020). https://doi.org/10.1038/s41417-019-0099-5

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