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Histone deacetylase (HDAC) inhibitors [1] are FDA approved for the treatment of lymphoid malignancies, including cutaneous T cell lymphoma (romidepsin, vorinostat) and multiple myeloma (panobinostat). While these agents have also undergone extensive clinical testing alone and in combination with a variety of other agents in solid tumors, clinical activity compelling enough to lead to FDA approval has been elusive. Until now it has been unclear why HDAC inhibitors as a class seem to be more active in lymphoid malignancies than in other neoplasms. Previous understanding of the action of HDAC inhibitors has been based on both the demonstration that they alter gene expression through their impact on histone acetylation [1] and the more recent recognition that they impact lysine acetylation of other cellular proteins, including heat shock protein 90 (HSP90). When HSP90 becomes lysine acetylated as a consequence of HDAC inhibition, it has been reported to release client proteins, leading to their degradation [2]. Additional studies have demonstrated that increased signaling through the mitogen-activated protein (MAP) kinase pathway can lead to HDAC inhibitor resistance [3]. How the effects of HDAC inhibitors on gene expression, MAP kinase signaling or HSP90 function leads to selective killing of malignant lymphoid cells has not been obvious. Recent studies by Ding et al. [4] provide new insight into this question as summarized in Fig. 1. Following up the observation that HDAC inhibitors upregulate the proapoptotic protein BIM [3-5], these investigators traced BIM upregulation, in part, to inhibition of MAP kinase signaling. Working their way upstream, Ding et al. identified two components of the MAPK pathway, the guanine nucleotide exchange factor RASGRP1 and the serine/threonine kinase RAF1, that are markedly downregulated in a variety of malignant human lymphoid lines by numerous HDAC inhibitors. Importantly, this downregulation occurred at the protein level without any substantive change in mRNA [4]. Further studies demonstrated that treatment with either HDAC inhibitors or the HSP90 inhibitor tanespimycin causes dissociation of HSP90 from RASGRP1 and RAF1, leading to degradation of both of these proteins. Particularly germane to the question of HDAC inhibitor selectivity, RASGRP1 is expressed almost exclusively in lymphoid cells [6], with higher levels in malignant T cells than in malignant B cells [7]. Without RASGRP1, RAS-mediated survival signaling is markedly diminished because of stabilization of the RAS•GDP complex [6]. These observations have potential implications not only for the mechanism of action of HDAC inhibitors, Editorial

Getting a GRP on histone deacetylase inhibitor selectivity