Selective JAK inhibition proves efficacious in epithelial cancer models

Abstract

14592 Background: Signal transducers and activators of transcription (STATs) are a family of latent transcription factors that are aberrantly activated in a diverse spectrum of epithelial tumors. STATs can be activated through tyrosine phosyporylation by a number of kinases including Janus kinases (JAKs), Src, Abl, and EGFR. Phosphorylated STATs (pSTAT) contribute to oncogenesis by preventing apoptosis and stimulating proliferation and angiogenesis. With the evolution of novel targeted therapies, identification of the kinases responsible for STAT activation in cancer cells may help pinpoint sites of potential therapeutic intervention. Methods: A number of potent, selective, orally bioavailable JAK inhibitors were utilized to treat a series of human epithelial cancer cell lines and tumor xenografts derived from breast, head and neck, prostate, stomach, lung, and renal tumors. In doing so, the contribution of JAK signaling to STAT phosphorylation was investigated as were the sequela of such inhibition. Results: Selective JAK inhibition frequently reduced the basal and/or cytokine stimulated levels of phosphorylated STAT3/5 by > 90 %. Oral administration of JAK inhibitors was also sufficient to reduce phosphorylated STAT levels in tumor xenografts and impeded tumor growth, including tumor regression (e.g., BT-474 breast HER2+ breast cancer). Moreover, selective JAK inhibition dramatically improved the anti-tumor activities of various ancillary therapies including targeted and cytotoxic drugs. Conclusions: Aberrant STAT activation has been associated with epithelial cancers and contributes to oncogenesis. Here we utilized pharmacological tools to query the role of JAKs in STAT activation and demonstrated that selective JAK inhibition is sufficient to inhibit STAT phosphorylation in cell lines and xenograft tumors from a spectrum of human cancers. Selective JAK inhibition impeded the growth of xenograft tumors and markedly improved the anti-tumor activity of standard chemotherapies and molecularly targeted agents. As such, selective JAK inhibitors may prove to have clinical utility for the treatment of a number of common cancers. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Incyte Incyte