Signal transduction activator of transcription (STAT) 3 is a member of the STAT protein family which transduces intracellular and extracellular signals to the nucleus, controlling the expression of genes responsible for multiple physiological processes. In contrast to the transient nature of physiological STAT3 signaling observed in normal cells, STAT3 is persistently activated in many malignancies, resulting in cell proliferation, survival, angiogenesis, and tumor-mediated immune evasion. Aberrant STAT3 activation in tumors can occur by canonical signaling (Figure 1), where cytoplasmic STAT3 monomers are phosphorylated by upstream signals, namely, cytokine or growth-factor activated Janus kinases (JAK), activated growth factor receptors (eg epidermal growth factor receptor [EGFR]), or nonreceptor tyrosine kinases (eg Src). Phosphorylated STAT3 (Tyr) 705 dimerize through reciprocal phosphotyrosine-SH2 linkage and translocate to the nucleus, where they promote transcription of target genes, including cell-cycle regulators, proto-oncogenes, and antiapoptotic genes. Noncanonical pathways of STAT3 signaling have also been shown to play a significant role in malignant transformation, independently of STAT3 (Tyr) 705 phosphorylation. STAT3 (Ser) 727 is located at an alternative C-terminus site, where it is phosphorylated by mitogen activated pathway (MAP) kinase, c-Jun N-terminal kinase or protein kinase C (PKC) signaling, leading to enhanced STAT3 target gene transcription. In addition, STAT3 dimer stability and activity can be modified by the reversible acetylation of the STAT3 lysine685 (K685). On the other hand, negative regulators of STAT3 are thought to be perturbed in malignancy. These include suppressors of cytokine signaling (SOCS), protein tyrosine phosphatases (PTPs), and sirtuin 1-induced K685 deacetylation [1]. STAT3 SH2 domain gainof-function mutations have been identified as oncogenic drivers of certain rare malignancies, for example, large granular lymphocytic leukemia [2]. However, these mutations are too rare to account for the high prevalence of STAT3 activation in solid tumors. Therefore, the main pathways contributing to STAT3 activation in cancers are the increased secretion of cytokines and growth factors in the tumor microenvironment, overexpression of protein tyrosine kinases, and epigenetic modulation of negative regulators of STAT3.

STAT3 is regarded as an important therapeutic target in cancer for several reasons. First, it is frequently activated in a wide range of malignancies, and in-vitro STAT3 inhibition leads to growth inhibition and apoptosis in many human cancer models [3]. Second, the inhibition of STAT3 signaling leads to selective apoptosis observed in STAT3-dependent tumor cells but not normal cells. Third, multiple oncogenic pathways converge on STAT3, hence its inhibition effectively blocks several upstream tyrosine kinases simultaneously. STAT3 has been shown to be a key mediator of the oncogenic effects of two prototypal oncogene-addicted tumors; EGFR mutationpositive non-small cell lung cancer (NSCLC) and BRAF-mutant malignant melanoma [4, 5]. More recently, STAT3 activation has been identified as a mechanism of resistance in oncogene-addicted phenotypes treated with their respective oncogenic pathway inhibitors. Primary pharmacological inhibition of various oncogene-driven models (EGFR, HER2, ALK, and MET) led to therapeutic resistance through upregulated STAT3 signaling, whereas disruption of the STAT3 feedback mechanism with FGFR/JAK1 inhibition restored sensitivity to their respective pathway inhibitors [6]. This has wide-ranging therapeutic implications …