Exploring Novel Frontiers: Leveraging STAT3 Signaling for Advanced Cancer Therapeutics

Abstract

Signal Transducer and Activator of Transcription 3 (STAT3) plays a significant role in diverse physiologic processes, including cell proliferation, differentiation, angiogenesis, and survival. STAT3 activation via phosphorylation of tyrosine and serine residues is a complex and tightly regulated process initiated by upstream signaling pathways with ligand binding to receptor and non-receptor-linked kinases. Through downstream deregulation of target genes, aberrations in STAT3 activation are implicated in tumorigenesis, metastasis, and recurrence in multiple cancers. While there have been extensive efforts to develop direct and indirect STAT3 inhibitors using novel drugs as a therapeutic strategy, direct clinical application remains in evolution. In this review, we outline the mechanisms of STAT3 activation, the resulting downstream effects in physiologic and malignant settings, and therapeutic strategies for targeting STAT3. We also summarize the pre-clinical and clinical evidence of novel drug therapies targeting STAT3 and discuss the challenges of establishing their therapeutic efficacy in the current clinical landscape.

Keywords: STAT3; cancer; therapeutics.

Figure 1

STAT protein family domain structure and function: The STAT protein family has a conserved structure characterized by six domains. N-terminal domain (NTD) facilitates STAT3 DNA promoter binding and assembly of transcriptional machinery. The coiled-coil domain (CCD) promotes STAT3 recruitment to the receptor and facilitates downstream interactions—phosphorylation, dimerization, nuclear translocation. The DNA-binding domain (DBD) is required for STAT3 binding to STAT3-regulated DNA sequence promoter. The linker domain connects the DBD to the SRC-homology-2 (SH2) domain. SH2 domain mediates receptor tyrosine phosphorylation and stabilizes dimerization of the STAT3 protein by interacting with phosphorylated tyrosine residues of a different STAT3 monomer. The carboxyl-terminal transactivation domain (TAD) contains tyrosine residue Tyr705 and Ser727 phosphorylation sites which are essential for the transcriptional activation of target genes. Created with BioRender.com.

Figure 2

STAT3 signaling pathway: STAT3 activation is initiated by upstream activity including ligand binding by (a) cytokines (IL-6 and non-IL-6 family members), (b) growth factors (EGF, FGF, etc.) to respective receptor-linked kinases, and (c) non-receptor-linked kinases (Scr, ABL). This triggers JAK activation through phosphorylation (p), with subsequent receptor tyrosine phosphorylation and STAT3 phosphorylation at Tyr705. Activated STAT3 forms homodimers which translocate to the nucleus, bind consensus DNA, and regulate the transcription of target genes. Three main endogenous proteins negatively regulate the physiologic activation of the STAT3 signaling pathway; SOCS (suppressor of cytokine signaling), PTPs (protein tyrosine phosphatase), and PIAS (protein inhibitor of activated STAT). SOCS and PTPs interact directly with respective tyrosine kinase receptors and JAK. SOCS block recruitment of STAT3 and inhibit JAK kinase activity while PTPs dephosphorylate related JAK and can directly dephosphorylate STAT3 dimers. PIAS prevents STAT3 dimers from binding DNA. Created with BioRender.com.

Figure 3

STAT3 inhibitors and mechanism of action: Constitutive activation of STAT3 can be disrupted indirectly or directly using novel drugs. Indirect inhibitors target upstream molecules such as IL-6, IL-6R, or JAK and include Tocilizumab, Siltuximab, Ruxolitinib. Direct inhibitors prevent STAT3 phosphorylation, dimerization, and target gene transcription. These include Stattic, OZD10117, OPB-51602, and PY*LKT. Other mechanisms of STAT3 inhibition involve targeting DNA-binding domains with molecules such as DNA decoy oligonucleotides. STAT3 mRNA may also be targeted using antisense oligonucleotides such as AZD9150. Created with BioRender.com.