Targeting the NF-?B pathway enhances responsiveness of mammary tumors to JAK inhibitors

Interactions between tumor cells and the tumor microenvironment are critical for tumor growth, progression, and response to therapy. Effective targeting of oncogenic signaling pathways in tumors requires an understanding of how these therapies impact both tumor cells and cells within the tumor microenvironment. One such pathway is the janus kinase (JAK)/signal transducer and activator or transcription (STAT) pathway, which is activated in both breast cancer cells and in tumor associated macrophages. This study demonstrates that exposure of macrophages to JAK inhibitors leads to activation of NF-?B signaling, which results in increased expression of genes known to be associated with therapeutic resistance. Furthermore, inhibition of the NF-?B pathway improves the ability of ruxolitinib to reduce mammary tumor growth in vivo. Thus, the impact of the tumor microenvironment is an important consideration in studying breast cancer and understanding such mechanisms of resistance is critical to development of effective targeted therapies. Overall design: Bone marrow mRNA profiles of 8-week old WT Balb/c mice treated with DMEM, 4T1 tumor conditioned media, ruxolitinib and IKK-16