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Cited by 24Cytokine Signaling Pathways and InteractionsProtein Tyrosine PhosphatasesCancer Mechanisms and Therapy

Critical analysis of the potential for targeting STAT3 in human malignancy

Open access
Grandis, Jennifer, Peyser·2013·OncoTargets and Therapy
DOI 10.2147/ott.s47903PMC PMC3735336
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Abstract

The signal transducer and activator of transcription (STAT) family of proteins was originally discovered in the context of normal cell biology where they function to transduce intracellular and extracellular signals to the nucleus, ultimately leading to transcription of specific target genes and downstream phenotypic effects. It was quickly appreciated that the STATs, especially STAT3, play a fundamental role in human malignancy. In contrast to normal biology in which transient STAT3 signaling is strictly regulated by a tightly coordinated network of activators and deactivators, STAT3 is constitutively activated in human malignancies. Constitutive STAT3 signaling has been associated with many cancerous phenotypes across nearly all human cancers, including the upregulation of cell growth, proliferation, survival, and motility, among others. Studies involving candidate preclinical STAT3 inhibitors have further demonstrated that the reversal of these phenotypes results from pharmacologic or genetic inhibition of STAT3, suggesting that STAT3 may be a promising target for clinical interventions. Indeed, a Phase 0 clinical trial involving a STAT3 decoy oligonucleotide demonstrated that STAT3 is a drug-gable target in human tumors. Because of the ubiquity of overactive STAT3 in cancer, its role in promoting a wide variety of cancerous phenotypes, and the strong clinical and preclinical studies performed to date, STAT3 represents a promising target for the development of inhibitors for the treatment of human cancers.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that STAT3 is a promising direct therapeutic target in human cancer because it is constitutively activated across many malignancies and drives proliferation, survival, motility, angiogenesis, immune suppression, and stem-cell maintenance. It summarizes preclinical and early clinical evidence, including a Phase 0 STAT3 decoy trial, while noting that most STAT3 inhibitors in clinical development have not yet reported results.

Key findings

  • STAT3 is overexpressed and/or hyperactivated in the majority of human cancers, but somatic mutation of STAT3 is rare: 1.08% (54/4980 tumors analyzed by whole-exome sequencing by The Cancer Genome Atlas).
  • Constitutive STAT3 signaling promotes cancerous phenotypes including cell growth/proliferation, apoptosis evasion, migration/invasion, angiogenesis, inflammation-associated carcinogenesis, suppression of antitumor immunity, and cancer stem cell maintenance.
  • A Phase 0 trial of an intratumoral STAT3 decoy oligonucleotide in head and neck squamous cell carcinoma patients decreased expression of STAT3 target genes relative to saline-injected tumors, demonstrating that STAT3 is druggable in human tumors.
  • Of four STAT3 inhibitor trials listed from clinicaltrials.gov, one was complete and three were recruiting or ongoing; no results had been published from the Isis, AstraZeneca, or Otsuka studies at the time of the review.

Methods

  • Narrative/critical review of STAT3 biology, cancer mechanisms, and therapeutic targeting, with no primary experimental data reported.
  • Evidence synthesized from preclinical models, human tumor studies, and clinical trial information from www.clinicaltrials.gov.
  • Main analysis is qualitative: the authors evaluate whether STAT3 meets criteria for an optimal cancer target and discuss inhibitor strategies including oligonucleotide decoys, antisense oligonucleotides, SH2-domain inhibitors, and small molecules.

Limitations

  • The paper states that no results have yet been published from three of the four clinical STAT3 inhibitor trials listed, and that the cyclic STAT3 decoy has not yet been tested in humans.
  • The paper notes that some areas remain incompletely understood, including context-specific consequences of STAT3 serine 727 phosphorylation and epigenomic alteration of proteins that normally inactivate STAT3.
  • Evident from the text: this is not a systematic review, with no stated search strategy, inclusion criteria, quality assessment, or quantitative synthesis; the clinical development overview is limited to a small number of trials and relies partly on a poster abstract.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.2147/ott.s47903

Cites

113 of 113 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

57 of 92 cited sources checked · 26 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    SOCS1 and SOCS3 inhibit STAT3 in a cytokine-inducible manner by binding to and inhibiting upstream JAKs.

    “The suppressor of cytokine signaling (SOCS) family of proteins, especially SOCS1 and SOCS3, inhibit STAT3 in a cytokine-inducible manner by binding to and inhibiting upstream JAKs.13,14”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [13] Sasaki A Yasukawa H Suzuki A Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain Genes Cells 1999 4 6 339 351 10421843 source
    • cites [14] Yasukawa H Misawa H Sakamoto H The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop EMBO J 1999 18 5 1309 1320 10064597 PMC1171221 source

      The Introduction identifies JAB as SOCS1, and the JAK-kinase Results section reports that JAB binds to and inhibits JAK2. The same Results section says CIS3 binds JAK2 weakly but did not inhibit its kinase activity in this assay. The passages do not establish inhibition of STAT3 by either protein or show that the inhibition itself is cytokine-inducible. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Activation of STAT3 signaling is a critical component of malignant transformation.

    “Further study revealed that STAT3 activation and specific gene regulation is required for Src-mediated transformation of NIH-3T3 cells, leading to the conclusion that activation of STAT3 signaling is a critical component of malignant transformation.42,43”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [42] Bromberg JF Horvath CM Besser D Lathem WW Darnell JE Stat3 activation is required for cellular transformation by v-src Mol Cell Biol 1998 18 5 2553 2558 9566875 PMC110635 source

      The Discussion (page not available in our copy) reports that activated Stat3 has oncogenic potential and that inhibiting Stat3 reduces v-src transformation in NIH 3T3 cells. The paper concludes that Stat3 activation is necessary for v-src transformation, but does not establish that it is required for malignant transformation generally; it reports no effect on v-ras transformation. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [43] Turkson J Bowman T Garcia R Caldenhoven E De Groot RP Jove R Stat3 activation by Src induces specific gene regulation and is required for cell transformation Mol Cell Biol 1998 18 5 2545 2552 9566874 PMC110634 source
  • Premisecitation

    Somatic mutation of the STAT3 gene in cancer is rare (1.08%; 54/4980 tumors analyzed to date by whole exome sequencing by The Cancer Genome Atlas).

    “The prevalence of STAT3 overactivation in cancer cannot be explained by mutational activation of STAT3 because somatic mutation of the STAT3 gene in cancer is rare (1.08%; 54/4980 tumors analyzed to date by whole exome sequencing by The Cancer Genome Atlas).38”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [38] Cerami E Gao J Dogrusoz U The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data Cancer Discov 2012 2 5 401 404 22588877 PMC3956037 source

      The portal description (section labelled Abstract; page unavailable) says it includes TCGA datasets and mutation data, but does not report STAT3 mutation prevalence. Searches of our copy for STAT3, 54/4980, 1.08%, and the claimed whole-exome tumor count found no passage supporting the figure or the explanation of STAT3 overactivation. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Premisecitation

    Activation of STAT3 in human cancers can result from genomic or epigenomic inactivation of proteins that normally downregulate STAT3 activity.

    “Conversely, activation of STAT3 in human cancers can result from genomic or epigenomic inactivation of proteins that normally downregulate STAT3 activity.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [16] Nallar SC Kalakonda S Lindner DJ Tumor-derived mutations in the gene associated with retinoid interferon-induced mortality (GRIM-19) disrupt its anti-signal transducer and activator of transcription 3 (STAT3) activity and promote oncogenesis J Biol Chem 2013 288 11 7930 7941 23386605 PMC3597830 source

      The Abstract (page unavailable) reports that somatic GRIM-19 mutations impair its ability to inhibit STAT3, supporting genomic inactivation as one route to increased STAT3 activity. The Discussion (page unavailable) also identifies loss of STAT3 inhibitors as a possible cause of constitutive activation. The cited passages do not establish epigenomic inactivation of those inhibitors; the methylation mentioned in the Discussion concerns STAT protein modification, not epigenomic silencing. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [61] He B You L Uematsu K SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer Proc Natl Acad Sci USA 2003 100 24 14133 14138 14617776 PMC283558 source

      The Abstract and Discussion report that promoter hypermethylation silences SOCS-3, a negative regulator of JAK/STAT signaling, and that restoring SOCS-3 reduces active STAT3 in lung cancer cells. This supports epigenetic inactivation as a possible route to STAT3 activation, but the supplied passages do not establish genomic inactivation as another route. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [63] Capello D Gloghini A Baldanzi G Alterations of negative regulators of cytokine signalling in immunodeficiency-related non-Hodgkin lymphoma Hematol Oncol 2013 31 1 22 28 22488585 source

      The Discussion (page not provided) reports that methylation and silencing of the negative regulator PTPN6/SHP1 are associated with STAT3-pathway activation in lymphomas, and suggests that this silencing may sustain activation. The paper also reports SOCS1 mutations, but does not show that genomic inactivation caused STAT3 activation in its cases. The claim therefore extends the paper’s evidence beyond epigenetic silencing in particular lymphomas. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    In neuroblastoma, frequent point mutation of the RTK anaplastic lymphoma kinase (ALK) in the kinase domain (F1174L) leads to constitutive activation of STAT3.

    “In neuroblastoma, frequent point mutation of the RTK anaplastic lymphoma kinase (ALK) in the kinase domain (F1174L) leads to constitutive activation of STAT3.50”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [50] George RE Sanda T Hanna M Activating mutations in ALK provide a therapeutic target in neuroblastoma Nature 2008 455 7215 975 978 18923525 PMC2587486 source

      The paper reports F1174L as the most common ALK mutation in its primary neuroblastoma samples (4/93 tumors) and finds STAT3 phosphorylation in IL-3-deprived Ba/F3 cells engineered to express F1174L (passages 3 and 5, section labeled Abstract). It also reports reduced STAT3 phosphorylation after ALK inhibition in F1174L neuroblastoma cell lines (passage 4). It does not directly establish constitutive STAT3 activation caused by F1174L in neuroblastoma tumors. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Premisecitation

    STAT3 is a druggable target in human tumors, as demonstrated by a Phase 0 clinical trial involving a STAT3 decoy oligonucleotide.

    “Indeed, a Phase 0 clinical trial involving a STAT3 decoy oligonucleotide demonstrated that STAT3 is a drug-gable target in human tumors.”
    • Also stated in: § Overview of the current STAT3 inhibitors in clinical development · boosted
      “Intratumoral injection of this molecule prior to surgical resection in head and neck squamous cell carcinoma (HNSCC) patients led to decreased expression of STAT3 target genes relative to saline-injected tumors in a Phase 0 trial, confirming the ability of the decoy to downregulate STAT3 signaling in human tumors.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [100] Sen M Thomas SM Kim S First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy Cancer Discov 2012 2 8 694 705 22719020 PMC3668699 source

  • May combine two claims.

    Premisecitation

    Activation of STAT3 is associated with emergent resistance to targeted therapies and decreased patient survival.

    “In addition, activation of STAT3 is associated with emergent resistance to targeted therapies and decreased patient survival.39,40”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [39] Wang Z Zhu S Shen M STAT3 is involved in esophageal carcinogenesis through regulation of Oct-1 Carcinogenesis 2013 34 3 678 688 23172665 source

      The section “STAT3 is hyperactivated in ESCC tissue with overexpression of Oct-1” (page not provided) reports shorter survival among patients whose tumors had high STAT3 phosphorylation. It does not report emergent resistance to targeted therapies; searches for targeted-therapy and drug resistance found no supporting passage. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [40] Sen M Joyce S Panahandeh M Targeting Stat3 abrogates EGFR inhibitor resistance in cancer Clin Cancer Res 2012 18 18 4986 4996 22825581 PMC3445706 source

      The Introduction and Discussion associate STAT3 activation with resistance to EGFR inhibitors, including acquired resistance, and the Discussion reports increased STAT3 activation in resistant cancer models. Neither section links STAT3 activation to decreased patient survival. Page numbers are unavailable in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    STAT3 is involved in inflammation-associated carcinogenesis, suppression of the antitumor immune response, and maintenance of cancer stem cells.

    “STAT3 is also involved in inflammation-associated carcinogenesis, suppression of the antitumor immune response, and maintenance of cancer stem cells.”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [94] Grivennikov S Karin E Terzic J IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer Cancer Cell 2009 15 2 103 113 19185845 PMC2667107 source

      The Discussion (page not provided) reports that STAT3 ablation in intestinal epithelial cells reduced tumor formation and growth in a mouse model of colitis-associated cancer, supporting its role in inflammation-associated carcinogenesis. The passages do not establish that STAT3 suppresses the antitumor immune response or maintains cancer stem cells; searches for those points found no supporting passage. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [95] Liang J Nagahashi M Kim EY Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer Cancer Cell 2013 23 1 107 120 23273921 PMC3578577 source

      The Introduction (page unavailable) links STAT3 activation to the development of colitis-associated cancer. The Discussion (page unavailable) reports that inhibiting STAT3 signaling elicits antitumor immunity, supporting a role in suppressing that response. The passages do not address maintenance of cancer stem cells. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [96] Burdelya L Kujawski M Niu G Stat3 activity in melanoma cells affects migration of immune effector cells and nitric oxide-mediated antitumor effects J Immunol 2005 174 7 3925 3931 15778348 PMC2632804 source
    • cites [98] Sherry MM Reeves A Wu JK Cochran BH STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells Stem Cells 2009 27 10 2383 2392 19658181 PMC4391626 source

      The Discussion (page unavailable) reports that inhibiting STAT3 causes glioblastoma stem cells to lose self-renewal potential, supporting the cancer-stem-cell component. It also discusses STAT3 in tumor formation, but does not establish the more specific claim of inflammation-associated carcinogenesis. No passage found supports suppression of the antitumor immune response. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Activation of JAK2 caused by the V617F mutation leads to constitutive activation of STAT3 and is associated with reduced survival in idiopathic myelofibrosis.

    “Activation of JAK2 caused by this mutation leads to constitutive activation of STAT3 and is associated with reduced survival in idiopathic myelofibrosis.54,55”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [52] Jones AV Kreil S Zoi K Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders Blood 2005 106 6 2162 2168 15920007 source

      The Discussion (page not supplied) says V617F has been shown to constitutively activate JAK2. The Introduction mentions STAT3 activation in some patients with myeloproliferative disorders, but does not link it specifically to V617F; the paper also does not report reduced survival in idiopathic myelofibrosis. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [53] Scott LM Campbell PJ Baxter EJ The V617F JAK2 mutation is uncommon in cancers and in myeloid malignancies other than the classic myeloproliferative disorders Blood 2005 106 8 2920 2921 16204151 source
    • cites [54] Campbell PJ Griesshammer M Döhner K V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis Blood 2006 107 5 2098 2100 16293597 source

      The Results and discussion report significantly poorer survival among patients with idiopathic myelofibrosis who were V617F-positive than among those who were V617F-negative (adjusted hazard ratio 3.30). The paper does not report that the mutation causes constitutive STAT3 activation; a search for STAT3 found no supporting passage. Page numbers were not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [55] Oku S Takenaka K Kuriyama T JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation Br J Haematol 2010 150 3 334 344 20553273 source

  • May combine two claims.

    Premisecitation

    STAT3 target genes MMP-2 and MMP-9 are upregulated in esophageal squamous carcinoma cells (Eca-109) that express high pSTAT3, and STAT3 knockdown leads to downregulation of MMP-2 and MMP-9, dysregulation of cell migration directionality, decreased migration speed, and disorganization of F-actin formation.

    “The STAT3 target genes MMP-2 and MMP-9 are upregulated in esophageal squamous carcinoma cells (Eca-109) that express high pSTAT3, and STAT3 knockdown by RNA interference in these cells leads to downregulation of MMP-2 and MMP-9, dysregulation of cell migration directionality, decreased migration speed, and disorganization of F-actin formation; this demonstrates a central role for STAT3 in MMP-2/9–”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [39] Wang Z Zhu S Shen M STAT3 is involved in esophageal carcinogenesis through regulation of Oct-1 Carcinogenesis 2013 34 3 678 688 23172665 source

  • May combine two claims.

    Premisecitation

    In esophageal squamous carcinoma cells (Eca-109), activation of STAT3 by IL-6 treatment suppresses apoptosis, and knockdown of either STAT3 or Oct-1 enhances apoptosis.

    “In these cells, activation of STAT3 by IL-6 treatment suppresses apoptosis as assessed by TUNEL staining, and knockdown of either STAT3 or Oct-1 by RNA interference enhances apoptosis.39”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [39] Wang Z Zhu S Shen M STAT3 is involved in esophageal carcinogenesis through regulation of Oct-1 Carcinogenesis 2013 34 3 678 688 23172665 source

  • May combine two claims.

    Premisecitation

    STAT3 is a critical driver of cell growth in cancer, but not in normal cells.

    “STAT3 is a critical driver of cell growth in cancer, but not in normal cells.68”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [68] Schlessinger K Levy DE Malignant transformation but not normal cell growth depends on signal transducer and activator of transcription 3 Cancer Res 2005 65 13 5828 5834 15994959 PMC2100417 source

      The Abstract reports that STAT3-null mouse fibroblasts grew normally, while STAT3 was required for v-src transformation and growth in soft agar and as tumors in mice. The Discussion describes this as a transformation-specific function. The claim extends those findings to cancer cells and normal cells generally, beyond the fibroblast models studied; page numbers are not available in the supplied copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The STAT3 target gene MYC is a potent promoter of cell growth and is required for Src-mediated cellular transformation via STAT3.

    “In addition, the STAT3 target gene MYC, which itself encodes a transcription factor, is also a potent promoter of cell growth and is required for Src-mediated cellular transformation via STAT3.45”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] Bowman T Broome MA Sinibaldi D Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis Proc Natl Acad Sci USA 2001 98 13 7319 7324 11404481 PMC34666 source

  • May combine two claims.

    Premisecitation

    In lung cancer, SOCS3 is frequently downregulated by promoter hypermethylation, and restoration of SOCS3 expression leads to downregulation of active STAT3, induction of apoptosis, and suppression of cell growth.

    “In lung cancer, for example, SOCS3 is frequently downregulated by promoter hypermethylation, and restoration of SOCS3 expression in cells where it was previously silenced leads to downregulation of active STAT3, induction of apoptosis, and suppression of cell growth.61”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [61] He B You L Uematsu K SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer Proc Natl Acad Sci USA 2003 100 24 14133 14138 14617776 PMC283558 source

  • May combine two claims.

    Premisecitation

    Constitutive STAT3 activation leads to evasion of apoptosis and a subsequent increase in cell survival.

    “Constitutive STAT3 activation leads to evasion of apoptosis and a subsequent increase in cell survival.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [77] Zhuang L Lee CS Scolyer RA Mcl-1, Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma Mod Pathol 2007 20 4 416 426 17384650 source

      The Discussion (page unavailable in our copy) reports that activated Stat3 is associated with higher expression of the antiapoptotic proteins Bcl-XL and Mcl-1 in melanoma; it also describes prior evidence that Stat3 activation upregulates both. The paper does not establish that constitutive STAT3 activation itself causes evasion of apoptosis and increased cell survival, so the claim states a stronger causal outcome than this source supports. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Treatment of cetuximab-resistant bladder cancer cell lines with elevated activated STAT3 leads to reduced cell viability and downregulation of STAT3 target genes.

    “Treatment of bladder cancer cell lines that are resistant to cetuximab and exhibit elevated levels of activated STAT3 relative to cetuximab-sensitive cell lines leads to reduced cell viability and downregulation of STAT3 target genes.40”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [40] Sen M Joyce S Panahandeh M Targeting Stat3 abrogates EGFR inhibitor resistance in cancer Clin Cancer Res 2012 18 18 4986 4996 22825581 PMC3445706 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Recent high throughput and in silico screens have the potential to identify novel strategies for targeting STAT3.

    “Recent high throughput and in silico screens also have the potential to identify novel strategies for targeting STAT3.101,106”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [101] Schust J Sperl B Hollis A Mayer TU Berg T Stattic: a small-molecule inhibitor of STAT3 activation and dimerization Chem Biol 2006 13 11 1235 1242 17114005 source
    • cites [106] Song H Wang R Wang S Lin J A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells Proc Natl Acad Sci USA 2005 102 13 4700 4705 15781862 PMC555708 source

  • May combine two claims.

    Interpretationcitation

    STAT3 inhibition may be effective at overcoming acquired resistance or as adjuvant therapy to prevent recurrence.

    “These results suggest that STAT3 inhibition may be effective at overcoming acquired resistance or as adjuvant therapy to prevent recurrence.40”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [40] Sen M Joyce S Panahandeh M Targeting Stat3 abrogates EGFR inhibitor resistance in cancer Clin Cancer Res 2012 18 18 4986 4996 22825581 PMC3445706 source

      The Discussion (page not provided) reports that targeting STAT3 sensitized EGFR-inhibitor-resistant cells to treatment and suggests it may overcome therapeutic resistance. The Results describe increased pSTAT3 in tumors that recurred after cetuximab, but the paper does not propose STAT3 inhibition as adjuvant therapy to prevent recurrence. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Intratumoral injection of the STAT3 decoy prior to surgical resection in HNSCC patients led to decreased expression of STAT3 target genes relative to saline-injected tumors in a Phase 0 trial, confirming the ability of the decoy to downregulate STAT3 signaling in human tumors.

    “Intratumoral injection of this molecule prior to surgical resection in head and neck squamous cell carcinoma (HNSCC) patients led to decreased expression of STAT3 target genes relative to saline-injected tumors in a Phase 0 trial, confirming the ability of the decoy to downregulate STAT3 signaling in human tumors.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [100] Sen M Thomas SM Kim S First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy Cancer Discov 2012 2 8 694 705 22719020 PMC3668699 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Antisense oligonucleotides are designed to cause degradation of STAT3 mRNA or prevent its translation via complementary base pairing, thereby reducing total STAT3 protein levels.

    “Other inhibition strategies include the introduction of antisense oligonucleotides, as in the case of the Isis Pharmaceuticals, Inc/AstraZeneca drug in clinical development, designed to cause degradation of STAT3 mRNA or prevent its translation via complementary base pairing, thereby reducing total STAT3 protein levels.105”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [105] Epling-Burnette PK Liu JH Catlett-Falcone R Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression J Clin Invest 2001 107 3 351 362 11160159 PMC199188 source

      The section “Antisense STAT3 reverses Fas resistance in leukemic LGLs” (page not supplied) reports that antisense STAT3 oligonucleotides reduced STAT3 protein levels by 25–45% in cells from three patients. It does not establish whether the reduction resulted from mRNA degradation or blocked translation through complementary base pairing, and it does not discuss the Isis Pharmaceuticals/AstraZeneca drug in clinical development. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In preclinical models, non-small cell cancer cell lines with mutations in select tyrosine kinases do not exhibit decreased STAT3 activation upon treatment with erlotinib, U0126, sunitinib, or crizotinib, though other downstream effects including downregulation of phosphatidylinositol 3-kinase signaling do occur.

    “Studies in preclinical models demonstrate that non-small cell cancer cell lines with mutations in select tyrosine kinases do not exhibit decreased STAT3 activation upon treatment with the respective targeted small molecules erlotinib (EGFR), U0126 (MEK1/2), sunitinib (PDGFRA), or crizotinib (MET), though other downstream effects of these inhibitors, including downregulation of phosphatidylinositol”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [108] Looyenga BD Hutchings D Cherni I Kingsley C Weiss GJ Mackeigan J STAT3 is activated by JAK2 independent of key oncogenic driver mutations in non-small cell lung carcinoma PLoS ONE 2012 7 2 e30820 22319590 PMC3271110 source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Systemic administration by intravenous injection of the cyclic decoy in murine xenograft models inhibited tumor growth and expression of STAT3 target genes, demonstrating a successful strategy to inhibit intratumoral STAT3 signaling via systemic administration.

    “Importantly, systemic administration by intravenous injection of the cyclic decoy in murine xenograft models inhibited tumor growth and expression of STAT3 target genes, demonstrating a successful strategy to inhibit intratumoral STAT3 signaling via systemic, rather than intratumoral, administration.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [100] Sen M Thomas SM Kim S First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy Cancer Discov 2012 2 8 694 705 22719020 PMC3668699 source

  • May combine two claims.

    Premisecitation

    The STAT3 protein is overexpressed and/or hyperactivated in the majority of human cancers.

    “The STAT3 protein is overexpressed and/or hyperactivated in the majority of human cancers.37”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Yu H Jove R The STATs of cancer – new molecular targets come of age Nat Rev Cancer 2004 4 2 97 105 14964307 source

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    STAT3 is a promising target for the development of inhibitors and is the focus of much ongoing research and drug development.

    “As such, STAT3 is a promising target for the development of inhibitors and is the focus of much ongoing research and drug development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    STAT3 activity can be modified by reversible acetylation of lysine 685 (K685), which is critical for the formation of stable STAT3 dimers and is required for cytokine-induced STAT3-mediated transcription.

    “In addition, STAT3 activity can be modified by reversible acetylation of lysine 685 (K685), an event that is critical for the formation of stable STAT3 dimers and is required for cytokine-induced STAT3-mediated transcription.11,12”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Wang R Cherukuri P Luo J Activation of Stat3 sequence-specific DNA binding and transcription by p300/CREB-binding protein-mediated acetylation J Biol Chem 2005 280 12 11528 11534 15649887 source
    • cites [12] Yuan ZL Guan YJ Chatterjee D Chin YE Stat3 dimerization regulated by reversible acetylation of a single lysine residue Science 2005 307 5707 269 273 15653507 source

  • May combine two claims.

    Premisecitation

    Upon STAT3 activation, dimers directly bind DNA at TT(N)4-6AA consensus sites and regulate transcription of specific target genes.

    “Upon STAT3 activation, dimers directly bind DNA at TT(N)4–6AA consensus sites and regulate transcription of specific target genes.7”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Ehret GB Reichenbach P Schindler U DNA binding specificity of different STAT proteins. Comparison of in vitro specificity with natural target sites J Biol Chem 2001 276 9 6675 6688 11053426 source

  • May combine two claims.

    Premisecitation

    PIAS3 binds specifically to STAT3 and abrogates its activity.

    “Members of the protein inhibitor of activated STAT (PIAS) family, especially PIAS3, are small ubiquitin-like modifier-E3 ligases that bind specifically to STAT3 and abrogate its activity.15”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Chung CD Liao J Liu B Specific inhibition of Stat3 signal transduction by PIAS3 Science 1997 278 5344 1803 1805 9388184 source

  • May combine two claims.

    Premisenone given

    STAT3 activation across tissues is a transient event, and STAT3 is quickly downregulated.

    “STAT3 activation across these tissues is a transient event, and STAT3 is quickly downregulated.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    When aberrations occur in the strict regulation of STAT3, malignancies can develop.

    “When aberrations occur in the strict regulation of STAT3, malignancies can develop.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    STAT3 is constitutively activated in human malignancies, in contrast to normal biology where transient STAT3 signaling is strictly regulated.

    “STAT3 is constitutively activated in human malignancies.”
    • Also stated in: § Genomic and epigenomic deregulation of STAT3 in cancer · plain
      “The STAT3 protein is overexpressed and/or hyperactivated in the majority of human cancers.37”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Yu H Jove R The STATs of cancer – new molecular targets come of age Nat Rev Cancer 2004 4 2 97 105 14964307 source

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The contribution of STAT proteins to cancer, especially overexpression and overactivation of STAT3, is crucial for the development and progression of many cancers.

    “It now appears that the contribution of STAT proteins to cancer, especially overexpression and overactivation of STAT3, is crucial for the development and progression of many cancers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    STAT3-mediated Bcl-2 expression in metastatic subclones of MDA-MB435 correlates with increased pSTAT3 and contributes to chemoresistance.

    “STAT3-mediated Bcl-2 expression in metastatic subclones of the parental cell line MDA-MB435 (estrogen receptor-negative breast cancer) correlates with increased pSTAT3, but not with other transcription factors that regulate Bcl-2, and contributes to chemoresistance in this cell line, suggesting that the antiapoptotic effects of STAT3 contribute to treatment sensitivity.80”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Real PJ Sierra A De Juan A Segovia JC Lopez-Vega JM Fernandez-Luna JL Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells Oncogene 2002 21 50 7611 7618 12400004 source

  • May combine two claims.

    Premisecitation

    Constitutively active STAT3 contributes to the cancer phenotype by promoting motility and invasion, including in human melanoma where increased activation of STAT3 promotes metastasis to the brain.

    “Constitutively active STAT3 further contributes to the cancer phenotype by promoting motility and invasion, including in human melanoma where increased activation of STAT3 promotes metastasis to the brain.82”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Xie TX Huang FJ Aldape KD Activation of stat3 in human melanoma promotes brain metastasis Cancer Res 2006 66 6 3188 3196 16540670 source

  • May combine two claims.

    Premisecitation

    The STAT3 target CCND1, encoding cyclin D1, is upregulated transcriptionally by active STAT3 and is required for STAT3-mediated transformation.

    “A critical mediator of cell growth downstream of STAT3 is its target CCND1, encoding gene cyclin D1, which is upregulated transcriptionally by active STAT3 and is required for STAT3-mediated transformation.74”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Leslie K Lang C Devgan G Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3 Cancer Res 2006 66 5 2544 2552 16510571 source

  • May combine two claims.

    Premisecitation

    STAT3 is persistently active in Wilms' tumor, where it transcriptionally upregulates the microRNA miR-370, which in turn regulates cell proliferation and tumorigenicity in mice.

    “For example, STAT3 is persistently active in Wilms’ tumor, a genetically heterogeneous childhood kidney cancer, where it transcriptionally upregulates the microRNA miR-370, which in turn regulates cell proliferation and tumorigenicity in mice.76”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Cao X Liu D Yan X Stat3 inhibits WTX expression through up-regulation of microRNA-370 in Wilms tumor FEBS Lett 2013 587 6 639 644 23333300 source

  • May combine two claims.

    Interpretationreasoning

    The contribution of STAT3 activation to tumor angiogenesis suggests that inhibition of STAT3 may be an efficient method to block angiogenesis and tumor progression.

    “The contribution of STAT3 activation to tumor angiogenesis, both in tumor cells and in endothelial cells, suggests that the inhibition of STAT3 may be an efficient method to block angiogenesis and tumor progression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Inhibition of STAT3 in preclinical models has demonstrated downregulation of cell growth/proliferation, motility/invasion, and angiogenesis, as well as upregulation of apoptosis, cell death, and the antitumor immune response across a wide variety of cancers.

    “The inhibition of STAT3 in preclinical models has demonstrated all these characteristics across a wide variety of cancers, most likely via reversal of the many mechanisms discussed previously in this review.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Preclinical data demonstrate potent and selective downregulation of STAT3 mRNA and protein following AZD9150 treatment in several murine models, including human tumor xenografts, resulting in strong antitumor activity.

    “Preclinical data recently reported in a poster abstract at the 2013 Annual Meeting of the American Association for Cancer Research demonstrate potent and selective downregulation of STAT3 mRNA and protein following AZD9150 treatment in several murine models, including human tumor xenografts. Downregulation resulted in strong antitumor activity and the study suggests that AZD9150 may be effective”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Kim Y Hsu J Zhou T Potent in vivo pharmacology of AZD9150, a next-generation, constrained ethyl-modified antisense oligonucleotide targeting STAT3 in multiple preclinical cancer models [abstract] Proceedings of the 104th Annual Meeting of the American Association for Cancer Research 2013 Apr 6–10 Washington, DC. Philadelphia (PA) AACR; 2013. Abstract nr LB-317

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These perceived difficulties have proven surmountable in the case of STAT3 in both preclinical and clinical models, with STAT3-targeting agents effectively downregulating the pathway and reversing its oncogenic effects.

    “These perceived difficulties have proven surmountable in the case of STAT3 in both preclinical and clinical models, with STAT3-targeting agents effectively downregulating the pathway and reversing its oncogenic effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    This challenge has been overcome both with oligonucleotide inhibitors, which exploit the exquisite specificity of the DNA-binding domain, and with recent high-throughput screens of compound libraries to identify candidates that specifically inhibit STAT3 and not STAT1.

    “This challenge has been overcome both with oligonucleotide inhibitors, which exploit the exquisite specificity of the DNA-binding domain, and with recent high-throughput screens of compound libraries to identify candidates that specifically inhibit STAT3 and not STAT1.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: STAT3 has structural homology with STAT1, a family member with tumor-suppressive properties in many systems.

  • May combine two claims.

    Interpretationcitation

    Many patients who initially respond to targeted therapies develop chemoresistance and secondary cancers that are associated with increased STAT3 signaling.

    “Though some patients initially respond to targeted therapies, many develop chemoresistance and secondary cancers that are associated with increased STAT3 signaling.”
    Quote in the paperSubstantial claim
36 of 36

  • The paper relies on this without support.

    Inhibiting STAT3 in human cancers will produce clinical benefit without unacceptable toxicity to normal tissues.

    “STAT3 represents a promising target for the development of inhibitors for the treatment of human cancers.”

  • The paper relies on this without support.

    STAT3 signaling is transient in normal tissues and cells.

    “In addition, because STAT3 signaling is transient in normal tissues and cells, the potential for adverse events following systemic administration of a STAT3 inhibitor is minimal.”

  • The paper relies on this without support.

    Many recently approved cancer therapies target tyrosine kinases that are upstream of STAT3 activation, among other pathways.

    “Many of the recently approved cancer therapies target tyrosine kinases that are upstream of STAT3 activation, among other pathways.”

  • The paper relies on this without support.

    Clinical success with these agents has been limited, although in some cases they do prove extremely effective.

    “Unfortunately, clinical success with these agents has been limited, although in some cases they do prove extremely effective.”

  • The paper relies on this without support.

    STAT3 and other transcription factors were widely regarded as untreatable with drugs mainly because they are not exposed to the extracellular surface and do not have clear ligand-binding domains that can be targeted for competitive inhibition.

    “Firstly, STAT3 and other transcription factors were widely regarded as untreatable with drugs mainly because they are not exposed to the extracellular surface and do not have clear ligand-binding domains that can be targeted for competitive inhibition.”

  • The paper relies on this without support.

    STAT3 has structural homology with STAT1, a family member with tumor-suppressive properties in many systems.

    “A second obstacle in targeting STAT3 was its structural homology with STAT1, a family member with tumor-suppressive properties in many systems.”

  • The paper relies on this without support.

    Many therapeutic clinical successes to date have been associated with decreased STAT3 signaling.

    “Indeed, many therapeutic clinical successes to date have been associated with decreased STAT3 signaling, but because of the diversity of signaling components upstream of STAT3, the high cost of developing inhibitors for each one, the potential for emergent compensatory mechanisms, and the development of resistance to a given therapy, directly targeting STAT3 will likely be a preferred strategy.”
7 of 7

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Authors
Grandis, J., & Peyser
Affiliations
University of Pittsburgh (US)
Venue
OncoTargets and Therapy
Publisher
Informa UK Limited
Published
2013-07
Volume
6
Pages
999
ISSN
1178-6930 (ISSN-L)
DOI
10.2147/ott.s47903
PMC
PMC3735336
OpenAlex
W1943378092
Cited by
24
References
115
Citations by year
2020: 1 · 2019: 2 · 2017: 4 · 2016: 4 · 2015: 7 · 2014: 6
FWCI
2.69
Type
journal article
Language
en
Open access
Licence
Locations
  • OncoTargets and Therapy (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Cancer Institute (P50 CA097190)
  • National Institute of Dental and Craniofacial Research (R01 DE023685)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
Keywords
STAT3, signal transducer and activator of transcription, constitutive STAT3 activation, cancer, STAT3 inhibitor, therapeutic target, tumor cell proliferation, tumor cell survival, tumor cell motility, signal transduction

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