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

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

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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.

Original languageEnglish (US)
Pages (from-to)1802-1814
Number of pages13
JournalOncogene
Volume38
Issue number11
DOIs
StatePublished - Mar 14 2019

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Guo, H., Zeng, D., Zhang, H., Bell, T., Yao, J., Liu, Y., Huang, S., Li, C. J., Lorence, E., Zhou, S., Gong, T., Jiang, C., Ahmed, M., Yao, Y., Nomie, K. J., Zhang, L., & Wang, M. (2019). Dual inhibition of PI3K signaling and histone deacetylation halts proliferation and induces lethality in mantle cell lymphoma. Oncogene, 38(11), 1802-1814. https://doi.org/10.1038/s41388-018-0550-3