Jak-STAT Inhibition Mediates Romidepsin and Mechlorethamine Synergism in Cutaneous T-Cell Lymphoma.

Abstract

Sézary syndrome is an aggressive and disseminated form of cutaneous T-cell lymphoma 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. In this study, we show synergistic antilymphoma effects of romidepsin in combination with mechlorethamine, an alkylating agent, in cutaneous T-cell lymphoma cell lines and primary samples with strong antitumor effects in an in vivo model of Sézary syndrome. Mechanistically, gene expression profiling points to abrogation of Jak/signal transducer and activator of transcription (STAT) signaling as an 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 Sézary syndrome samples, but not in romidepsin-resistant tumors. Moreover, in further support of Jak/STAT signaling as a modulator of romidepsin activity in cutaneous T-cell lymphoma, 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 cutaneous T-cell lymphoma and uncover a previously unrecognized role for Jak/STAT signaling in the response to romidepsin and romidepsin-based combination therapies in Sézary syndrome.

• Authors: Jose R Cortes, Christina C Patrone, Stuart Aidan Quinn, Yuhan Gu, Marta Sanchez-Martin, Adam Mackey, Anisha J Cooke, Bobby B Shih, Anouchka P Laurent, Megan H Trager, Adolfo A Ferrando, Larisa J Geskin, Teresa Palomero
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 141 Issue 12 Pg. 2908-2920.e7 (12 2021) ISSN: 1523-1747 [Electronic] United States
• PMID: 34089720 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Depsipeptides
• Janus Kinase Inhibitors
• STAT Transcription Factors
• Mechlorethamine
• romidepsin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Cell Line, Tumor
• Depsipeptides (administration & dosage)
• Drug Synergism
• Humans
• Janus Kinase Inhibitors (pharmacology)
• Lymphoma, T-Cell, Cutaneous (drug therapy)
• Mechlorethamine (administration & dosage)
• Mice
• STAT Transcription Factors (antagonists & inhibitors, physiology)
• Signal Transduction (drug effects)
• Skin Neoplasms (drug therapy)