JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors

• DOI: 10.1073/pnas.1816410116
• Publication Date: 2019-05-31T00:45:35Z
• Authors: Emily A. Irey; Chelsea M. Lassiter; Nicholas J. Brady; Pavlina Chuntova; Ying Wang; Todd P. Knutson; Christine Henzler; Thomas S. Chaffee; Rachel I. Vogel; Andrew C. Nelson; Michael A. Farrar; Kathryn L. Schwer...
• Keywords: Ruxolitinib; Janus kinase 1

Tumor-associated macrophages contribute to tumor progression and therapeutic resistance in breast cancer. Within the microenvironment, tumor-derived factors activate pathways that modulate macrophage function. Using vitro vivo models, we find induce activation of Janus kinase (JAK)/signal transducer activator transcription 3 (STAT3) pathway macrophages. We also demonstrate loss STAT3 myeloid cells leads enhanced mammary tumorigenesis. Further studies show tumors JAK/STAT inhibitor ruxolitinib ruxolitinib-treated produce soluble promote JAK inhibition vitro. Finally, deletion increases expression protumorigenic factor cyclooxygenase-2 (COX-2), COX-2 enhances responsiveness ruxolitinib. These findings define a mechanism through which highlight importance understanding impact targeted therapies on microenvironment.