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Article type: Research Article
Authors: Sonkin, Dmitriya; 1 | Palmer, Michaelb; 1 | Rong, Xianhuib | Horrigan, Kimb | Regnier, Catherine H.c | Fanton, Christied | Holash, Jocelynd | Pinzon-Ortiz, Mariab | Squires, Matthewe | Sirulnik, Andrese | Radimerski, Thomasc | Schlegel, Robertb | Morrissey, Michaela | Cao, Z. Alexanderb; *
Affiliations: [a] Novartis Institutes for Biomedical Research, Cambridge, MA, USA | [b] Novartis Oncology Translational Medicine, Cambridge, MA, USA | [c] Novartis Institutes for Biomedical Research, Basel, Switzerland | [d] Novartis Institutes for Biomedical Research, Emeryville, CA, USA | [e] Novartis Oncology Global Development, Cambridge, MA, USA
Correspondence: [*] Corresponding author: Alexander Cao, Oncology Translational Research, Novartis Institute of Biomedical Research, 250 Massachusetts Ave., Cambridge, MA 02139, USA. Tel.: +1 617 871 3605; E-mail: [email protected].
Note: [1] These two authors contributed equally to this manuscript.
Abstract: Background:The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. Dysregulated JAK-STAT signaling has been implicated in the pathogenesis of multiple human malignancies. Objective:Given this pivotal role of JAK-STAT dysregulation, it is important to identify patients with an overactive JAK-STAT pathway for possible treatment with JAK inhibitors. Methods:We developed a gene signature assay to detect overactive JAK-STAT signaling. The cancer cell line encyclopedia and associated gene-expression data were used to correlate the activation status of STAT5 with the induction of a set of STAT5 target genes. Results:Four target genes were identified (PIM1, CISH, SOCS2, and ID1), the expression of which correlated significantly with pSTAT5 status in 40 hematologic tumor cell lines. In pSTAT5-positive models, the expression of the gene signature genes decreased following ruxolitinib treatment, which corresponded to pSTAT5 downmodulation. In pSTAT5-negative cell lines, neither pSTAT5 modulation nor a change in signature gene expression was observed following ruxolitinib treatment. Conclusions:The gene signature can potentially be used to stratify or enrich for patient populations with activated JAK-STAT5 signaling that might benefit from treatments targeting JAK-STAT signaling. Furthermore, the 4-gene signature is a predictor of the pharmacodynamic effects of ruxolitinib.
Keywords: Ruxolitinib, JAK-STAT, pSTAT5, gene signature
DOI: 10.3233/CBM-140434
Journal: Cancer Biomarkers, vol. 15, no. 1, pp. 79-87, 2015
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