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Dual inhibition of PI3K signaling and histone deacetylation halts proliferation and induces lethality in mantle cell lymphoma

Oncogene volume 38, pages 1802–1814 (2019)Cite this article

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Abstract

The dysregulation of PI3K signaling has been implicated as an underlying mechanism associated with resistance to Bruton’s tyrosine kinase inhibition by ibrutinib in both chronic lymphocytic leukemia and mantle cell lymphoma (MCL). Ibrutinib resistance has become a major unmet clinical need, and the development of therapeutics to overcome ibrutinib resistance will greatly improve the poor outcomes of ibrutinib-exposed MCL patients. CUDC-907 inhibits both PI3K and HDAC functionality to exert synergistic or additive effects. Therefore, the activity of CUDC-907 was examined in MCL cell lines and patient primary cells, including ibrutinib-resistant MCL cells. The efficacy of CUDC-907 was further examined in an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model. The molecular mechanisms by which CUDC-907 dually inhibits PI3K and histone deacetylation were assessed using reverse protein array, immunoblotting, and chromatin immunoprecipitation (ChIP) coupled with sequencing. We showed evidence that CUDC-907 treatment increased histone acetylation in MCL cells. We found that CUDC-907 caused decreased proliferation and increased apoptosis in MCL in vitro and in vivo MCL models. In addition, CUDC-907 was effective in inducing lethality in ibrutinib-resistant MCL cells. Lastly, CUDC-907 treatment increased histone acetylation in MCL cells. Overall, these studies suggest that CUDC-907 may be a promising therapeutic option for relapsed or resistant MCL.

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Data availability

All sequencing data will be deposited in the NCBI database of Genotypes and Phenotypes (dbGap, http://www.ncbi.nlm.nih.gov/gap). The data can be accessed under the accession number phs# (the submission process is currently ongoing, and the accession number is going to be updated once it is complete).

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Acknowledgements

This study was supported by the NIH-funded Cancer Center Support Grant (CCSG) P30 CA016672 and the R21 CA202104 (Michael Wang, PI). This study was also partially supported by the generous philanthropic support to the MD Anderson B Cell Lymphoma Moon Shot Project and philanthropy funds from The Gary Rogers Foundation and the Kinder Foundation. Pharmacyclics, an AbbVie Company, also provided funds for this laboratory work. The reagent CUDC-907 was provided by Curis, Inc. The laboratory research was not supported by Curis, Inc. Ibrutinib was provided by Pharmacyclics, an AbbVie Company. Cell line authentication was performed by the MD Anderson Cancer Center Characterized Cell Line Core Facility, funded by grant NCI # CA016672.

Author contributions

HG wrote the first draft of the manuscript; HG, KJN, EL, and MW wrote and revised the manuscript; HG, KJN, ZL, and MW conceived experiments; HG, DZ, HZ, TB, YL, YY, SH, CJL, EL, TG, CJ, MA, KJN, LZ, and MW carried out experiments and data analysis; JY performed bioinformatic analyses; SZ performed the statistical analysis. All authors have read and approved of the final manuscript.

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Authors and Affiliations

  1. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Hui Guo, Dongfeng Zeng, Hui Zhang, Taylor Bell, Yang Liu, Shengjian Huang, Carrie J. Li, Elizabeth Lorence, Changying Jiang, Makhdum Ahmed, Yixin Yao, Krystle J. Nomie, Liang Zhang & Michael Wang

  2. Department of Hematology, Xinqiao Hospital, The Third Military Medical University, 430000, Chongqing, China

    Dongfeng Zeng

  3. Department of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jun Yao

  4. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Shouhao Zhou

  5. Institute of Hematology & Oncology, The First Hospital of Harbin, 150010, Harbin, China

    Tiejun Gong

  6. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Michael Wang

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Correspondence to Michael Wang.

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Guo, H., Zeng, D., Zhang, H. et al. Dual inhibition of PI3K signaling and histone deacetylation halts proliferation and induces lethality in mantle cell lymphoma. Oncogene 38, 1802–1814 (2019). https://doi.org/10.1038/s41388-018-0550-3

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