The STAT3 pathway as a therapeutic target in head and neck cancer: Barriers and innovations

Abstract

Proteins of the signal transducer and activator of transcription (STAT) family mediate cellular responses to cytokines and growth factors. Aberrant regulation of the STAT3 oncogene contributes to tumor formation and progression in many cancers, including head and neck squamous cell carcinoma (HNSCC), where hyperactivation of STAT3 is implicated in both treatment resistance and immune escape. There are no oncogenic gain-of-function mutations in HNSCC. Rather, aberrant STAT3 signaling is primarily driven by upstream growth factor receptors, such as Janus kinase (JAK) and epidermal growth factor receptor (EGFR). Moreover, genomic silencing of select protein tyrosine phosphatase receptors (PTPRs), tumor suppressors that dephosphorylate STAT3, may lead to prolonged phosphorylation and activation of STAT3. This review will summarize current knowledge of the STAT3 pathway and its contribution to HNSCC growth, survival, and resistance to standard therapies, and discuss STAT3-targeting agents in various phases of clinical development.

Keywords: Head and neck cancer; STAT3.

Fig. 1

Schematic of the STAT3 pathway and therapeutic targets. (1) Cytokines and growth factors, such as IL-6 and EGF, bind to receptors to activate phosphorylation and cell signaling. Curcumin inhibits cell surface signaling, (2) STAT3 molecules are activated by phosphorylation of a tyrosine residue by activated RTKs, such as EGFR, or intracellular NRTKs like JAK or Src. Inactivation by dephosphorylation occurs by PTPRs. Targeted therapies, including the JAK1/2 inhibitor ruxolitinib, inhibit these pathways. (3) Spontaneous dimerization of two phosphorylated STAT3 molecules occurs via the reciprocal phosphotyrosine-SH2 interactions, and the homodimer translocates to the nucleus. Golotimod, an immunomodulating peptide, inhibits homodimerization of STAT3 molecules in the cytoplasm. (4) pSTAT3 homodimer binds to consensus sequences on the promotor regions of target genes. STAT3 decoy molecules are under development to target this step in the STAT3 transcription pathway. (5) The resultant transcripts are translated into pro-proliferative, pro-survival oncogenic proteins. (6) AZD9150 is an antisense oligonucleotide that inhibits the translation of STAT3 mRNA.