Constitutive activation of signal transducers and activators of transcription predicts vorinostat resistance in cutaneous T-cell lymphoma.
Vorinostat is a histone deacetylase inhibitor that induces differentiation, growth arrest, and/or apoptosis of malignant cells both in vitro and in vivo and has shown clinical responses in approximately 30% of patients with advanced mycosis fungoides and Sézary syndrome cutaneous T-cell lymphoma (CTCL). The purpose of this study was to identify biomarkers predictive of vorinostat response in CTCL using preclinical model systems and to assess these biomarkers in clinical samples. The signal transducer and activator of transcription (STAT) signaling pathway was evaluated. The data indicate that persistent activation of STAT1, STAT3, and STAT5 correlate with resistance to vorinostat in lymphoma cell lines. Simultaneous treatment with a pan-Janus-activated kinase inhibitor resulted in synergistic antiproliferative effect and down-regulation of the expression of several antiapoptotic genes. Immunohistochemical analysis of STAT1 and phosphorylated tyrosine STAT3 (pSTAT3) in skin biopsies obtained from CTCL patients enrolled in the vorinostat phase IIb trial showed that nuclear accumulation of STAT1 and high levels of nuclear pSTAT3 in malignant T cells correlate with a lack of clinical response. These results suggest that deregulation of STAT activity plays a role in vorinostat resistance in CTCL, and strategies that block this pathway may improve vorinostat response. Furthermore, these findings may be of prognostic value in predicting the response of CTCL patients to vorinostat.
Fantin
Valeria R
VR
Merck Research Laboratories, Harvard Medical School, Boston, Massachusetts, USA. valeria_fantin@merck.com
Loboda
Andrey
A
Paweletz
Cloud P
CP
Hendrickson
Ronald C
RC
Pierce
Jacqueline W
JW
Roth
Jennifer A
JA
Li
Lixia
L
Gooden
Frank
F
Korenchuk
Susan
S
Hou
Xiaoli S
XS
Harrington
Elizabeth A
EA
Randolph
Sophia
S
Reilly
John F
JF
Ware
Christopher M
CM
Kadin
Marshall E
ME
Frankel
Stanley R
SR
Richon
Victoria M
VM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D016393:Lymphoma, B-Cell / Q000188:drug therapy; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000378:metabolism*; D011379:Prognosis; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy*; D000077337:Vorinostat
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D006877:Hydroxamic Acids; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D000077337:Vorinostat