The role of STAT3 signaling in mediating tumor resistance to cancer therapy.

Signal transducer and activator of transcription 3 (STAT3) is activated in many cancer types and can regulate pathways involving tumorigenesis, cell proliferation, cell survival and angiogenesis. Upstream cytokine signaling through multiple trans-membrane receptors can enhance the activation of STAT3 and promote tumor progression. Importantly, STAT3 activation can also be induced via the Janus-activated kinase 1/2 (JAK1/2) and Src family kinases. Target-specific drug therapies have been developed to inhibit many of the upstream receptor and non-receptor activators of STAT3 and are now approved for clinical use. Recently, resistance to standard-of-care therapies has been linked to constitutive or unabated STAT3 activation, suggesting that combination therapy with STAT3 inhibitors may be of clinical benefit. Furthermore, STAT3 activity has also been shown to regulate self-renewal of cancer stem cells that are often refractory to chemotherapy treatment. This review will focus on STAT3 mediated resistance to cancer therapy and discuss strategies to overcome this resistance.