Editors' ChoiceCancer therapy

HDAC inhibitors in solid tumors and blood cancers

Sci. Signal.  20 Sep 2016:
Vol. 9, Issue 446, pp. ec216
DOI: 10.1126/scisignal.aaj2316

Histone deacetylase (HDAC) inhibitors have been approved for clinical treatment of various hematological cancers and are being explored for their utility in solid tumors. Two articles now reveal greater insight into the mechanistic basis of their efficacy in a subset of lymphoma patients and a possible mechanism for their failure in breast cancer patients. Using CD4+ T cells from the peripheral blood of cutaneous T cell lymphoma (CTCL) patients and control donors, Mishra et al. found that cells from CTCL patients had greater DNA methylation in the promoter of IL15, which encodes the cytokine interleukin 15 (IL-15) and is overexpressed in CTCL. DNA methylation can block the binding of transcription factors. Indeed, binding of the transcriptional repressor ZEB1 to the IL15 promoter was decreased in cells from CTCL patients compared with the binding at this promoter in cells from normal donors. Consequently, increased IL-15 production and autocrine signaling in CTCL cells reduced the binding of HDAC1 to its own promoter, as well as to the promoters of the genes encoding HDAC6 and miR-21, a microRNA associated with oncogenesis. The abundance of HDAC1, HDAC6, and miR-21 was increased in CTCL patient samples. Overexpression of Il15 in transgenic mice recapitulated CTCL development, the progression of which was suppressed by HDAC1 or HDAC6 inhibitors. The findings may explain why pan-HDAC inhibitors are effective and approved for use in CTCL patients and indicate that isotype-specific inhibitors could be a more targeted strategy with fewer side effects.

In contrast to the success with lymphoma, solid tumors have shown limited response to HDAC inhibitors. Zeng et al. revealed how HDAC inhibitor therapy might be improved through a combination strategy, at least for triple-negative breast cancer (TNBC) patients. In cultured TNBC cells, HDAC inhibition with vorinostat, the drug approved for CTCL, increased the expression of genes encoding proteins involved in cytokine signaling, including leukemia inhibitory factor receptor (LIFR) and anti-apoptotic proteins, particularly BCL-2 and MCL-1. BCL-2 and MCL-1 are encoded by genes stimulated by the Janus kinase (JAK)–signal transducer and activator of transcription (STAT3) cascade downstream of LIFR and other cytokine receptors. Various experiments indicated that the LIF-LIFR-STAT3 anti-apoptotic pathway is a drug-induced feedback resistance mechanism mediated by increased histone acetylation of the LIFR promoter and its transcriptional activation by the acetyllysine reader BRD4. Knocking down BRD4 prevented vorinostat-induced STAT3 phosphorylation, but BRD4 inhibitors are not yet approved for clinical use. Instead, blocking the resistance mechanism downstream using the approved JAK inhibitor INCB018424 sensitized various TNBC cell lines and patient-derived xenografts to vorinostat, suggesting that this combination therapy may improve the clinical utility of HDAC inhibitors in TNBC patients.

A. Mishra, K. La Perle, S. Kwiatkowski, L. A. Sullivan, G. H. Sams, J. Johns, D. P. Curphey, J. Wen, K. McConnell, J. Qi, H. Wong, G. Russo, J. Zhang, G. Marcucci, J. E. Bradner, P. Porcu, M. A. Caligiuri, Mechanism, consequences, and therapeutic targeting of abnormal IL15 signaling in cutaneous T-cell lymphoma. Cancer Discov. 6, 986–1005 (2016). [PubMed]

H. Zeng, J. Qu, N. Jin, J. Xu, C. Lin, Y. Chen, X. Yang, X. He, S. Tang, X. Lan, X. Yang, Z. Chen, M. Huang, J. Ding, M. Geng, Feedback activation of leukemia inhibitory factor receptor limits response to histone deacetylase inhibitors in breast cancer. Cancer Cell 30, 459–473 (2016). [PubMed]