83JAK-STAT inhibition mediates romidepsin and mechlorethamine synergism in Cutaneous T-cell Lymphoma.

Abstract

Sézary Syndrome (SS) is an aggressive and disseminated form of Cutaneous T-cell lymphoma (CTCL) associated with dismal prognosis in which the histone deacetylase inhibitor romidepsin, has shown remarkable activity as a single agent. However, clinical responses to romidepsin are typically transient, highlighting the need for more effective therapies. Here, we show synergistic anti-lymphoma effects of romidepsin in combination with mechlorethamine, an alkylating agent, in CTCL cell lines and primary samples with strong antitumor effects in an in vivo model of SS. Mechanistically, gene expression profiling points to abrogation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling as important mediator of this interaction. Consistently, the combination of mechlorethamine plus romidepsin resulted in downregulation of STAT5 phosphorylation in romidepsin-sensitive cell lines and primary SS samples, but not in romidepsin-resistant tumors. Moreover, and in further support of JAK/STAT signaling as a modulator of romidepsin activity in CTCL, treatment with romidepsin in combination with JAK inhibitors resulted in markedly increased therapeutic responses. Overall, these results support a role for romidepsin plus mechlorethamine in combination in the treatment of CTCL and uncover a previously unrecognized role for JAK-STAT signaling in the response to romidepsin and romidepsin-based combination therapies in SS.