Selective inhibition of HDAC6 sensitizes CTCL to PI3K inhibitors

Aims: Histone deacetylase (HDAC) inhibitors registered in CTCL are non-selective agents with unsatisfactory response and considerable side effects. Targeting single HDAC isoforms is believed to provide novel therapeutic options. HDAC6 is overexpressed in primary samples from CTCL patients. Recently, HDAC6 inhibitor has been reported to delay tumor development in transgenic mice overexpressing IL-15 that spontaneously develop a CTCL-like disease, suggesting that combinations including HDAC6 inhibitors may be successful in the treatment of CTCL. PI3K inhibition is currently tested in clinical trials in CTCL with encouraging results. Moreover, a hybrid HDAC-PI3K inhibitor is already being clinically evaluated in other types of lymphoma. As HDAC6 is known to deacetylate Akt diminishing its activation, the aim of this study was to evaluate the therapeutic potential of selective HDAC6 inhibitors in combination with PI3K inhibitors in CTCL.