mTOR kinase inhibitors synergize with histone deacetylase inhibitors to kill B-cell acute lymphoblastic leukemia cells

Brandon R. Beagle, Duc M. Nguyen, Sharmila Mallya, Sarah S. Tang, Mengrou Lu, Zhihong Zeng, Marina Konopleva, Thanh Trang Vo, David A. Fruman

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

High activity of the mechanistic target of rapamycin (mTOR) is associated with poor prognosis in pre-B-cell acute lymphoblastic leukemia (B-ALL), suggesting that inhibiting mTOR might be clinically useful. However, emerging data indicate that mTOR inhibitors are most effective when combined with other target agents. One strategy is to combine with histone deacetylase (HDAC) inhibitors, since B-ALL is often characterized by epigenetic changes that silence the expression of pro-apoptotic factors. Here we tested combinations of mTOR and pan-HDAC inhibitors on B-ALL cells, including both Philadelphia chromosome-positive (Ph+) and non-Ph cell lines. We found that mTOR kinase inhibitors (TOR-KIs) synergize with HDAC inhibitors to cause apoptosis in B-ALL cells and the effect is greater when compared to rapamycin plus HDAC inhibitors. The combination of TOR-KIs with the clinically approved HDAC inhibitor vorinostat increased apoptosis in primary pediatric B-ALL cells in vitro. Mechanistically, TOR-KI and HDAC inhibitor combinations increased expression of pro-death genes, including targets of the Forkhead Box O (FOXO) transcription factors, and increased sensitivity to apoptotic triggers at the mitochondria. These findings suggest that targeting epigenetic factors can unmask the cytotoxic potential of TOR-KIs towards B-ALL cells.

Original languageEnglish (US)
Pages (from-to)2088-2100
Number of pages13
JournalOncotarget
Volume6
Issue number4
DOIs
StatePublished - 2015

All Science Journal Classification (ASJC) codes

  • Oncology

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    Beagle, B. R., Nguyen, D. M., Mallya, S., Tang, S. S., Lu, M., Zeng, Z., Konopleva, M., Vo, T. T., & Fruman, D. A. (2015). mTOR kinase inhibitors synergize with histone deacetylase inhibitors to kill B-cell acute lymphoblastic leukemia cells. Oncotarget, 6(4), 2088-2100. https://doi.org/10.18632/oncotarget.2992