Abstract
Simple SummaryPersistent activation of STAT3 is frequently observed in non-small cell lung cancer and is associated with a poor prognosis. Given the multifaceted role of STAT3 signaling in NSCLC tumor development and progression, this pathway represents a promising therapeutic target for anti-cancer therapy. In this review, we discuss the molecular and immunological mechanisms by which persistent STAT3 activation promotes NSCLC development, and the utility of STAT3 as a prognostic and predictive biomarker. We also provide an update of STAT3-targeting therapies that are currently undergoing Phase I/II clinical trials, and discuss the challenges associated with these treatment modalities in the clinic.Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for 85% of lung cancer cases. Aberrant activation of the Signal Transducer and Activator of Transcription 3 (STAT3) is frequently observed in NSCLC and is associated with a poor prognosis. Pre-clinical studies have revealed an unequivocal role for tumor cell-intrinsic and extrinsic STAT3 signaling in NSCLC by promoting angiogenesis, cell survival, cancer cell stemness, drug resistance, and evasion of anti-tumor immunity. Several STAT3-targeting strategies have also been investigated in pre-clinical models, and include preventing upstream receptor/ligand interactions, promoting the degradation of STAT3 mRNA, and interfering with STAT3 DNA binding. In this review, we discuss the molecular and immunological mechanisms by which persistent STAT3 activation promotes NSCLC development, and the utility of STAT3 as a prognostic and predictive biomarker in NSCLC. We also provide a comprehensive update of STAT3-targeting therapies that are currently undergoing clinical evaluation, and discuss the challenges associated with these treatment modalities in human patients.
Highlights
Treatment modalities for advanced Non-small cell lung cancer (NSCLC) have evolved from traditional chemotherapies such as cytotoxic platinum-based drugs towards more effective regimens that are targeted towards specific molecular subtypes, including those that display epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK)
Treatment of tumor-bearing mice with the Signal Transducer and Activator of Transcription 3 (STAT3) inhibitor LL1 sensitizes resistant A549 NSCLC tumors to gefitinib and leads to a synergistic anti-tumor response [264,265]. These findings were corroborated in a separate study, where treatment of gefitinib- and erolotinib-resistant NSCLC with the STAT3 inhibitor W2014-S sensitized these cells to therapy in vitro and enhanced the anti-tumor efficacy of gefitinib in tyrosine kinase resistant lung cancer xenografts in vivo [238]
Aberrant activation of STAT3 plays a role in mediating chemoresistance in NSCLC, and over-expression of STAT3 is associated with cisplatin resistance in NSCLC cells [269,270]
Summary
Activation of STAT3 is triggered by a diverse range of cytokines, growth factors, and hormones [17], and can occur via several pathways (Figure 2) Receptor tyrosine kinases such as EGFR and vascular endothelial growth factor receptor (VEGFR) have intrinsic kinase domains and can directly phosphorylate STAT3 following ligand binding [18,19]. STAT3 homoand heterodimers are actively transferred to the nucleus where they bind to TTC(n) GAA consensus binding sites in the promoter and enhancer regions of target genes and modulate transcription [17,23] Certain cytokines such as IL6 and IL11 can promote STAT3 activation via an alternative trans-signaling pathway [24] (Figure 2). SOCS3 disrupts STAT3 signaling by directly inhibiting JAK activity, by competing with STAT3 for phosphotyrosine residues on receptor chains, and by binding to signaling proteins to trigger their proteasomal degradation [29,30]
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