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STAT3 as a target in anti-cancer therapy

We are studying the mechanisms of STAT3-regulated transcription and its involvement in cancer progression and therapy resistance.

Transcription factor STAT3 is activated in a large variety of tumors down-stream of receptor- and non-receptor tyrosine kinases (TK), such as Src, EGF-R and JAKs, stimulated by growth factors (GF) and cytokines. Phosphorylated STAT3 binds as a dimer to specific DNA elements in promoters to induce transcription of genes. An abnormal activation of STAT3 has been detected at high frequency in many solid and liquid tumors. STAT3-induced genes regulate a variety of processes such as proliferation, inhibition of apoptosis, epithelial-mesenchymal transition, tumor angiogenesis, and tumor-associated inflammation as well as contribute to immune escape. STAT3 is also an important factor for maintenance of cancer stem cells, CSCs. IL-6 and other cytokines that engage gp130 are major activators of STAT3 in cancer. IL-6 is necessary for the maintenance of CSCs and governs stroma-tumor interaction, cancer-associated inflammation and resistance to anti-cancer therapy [1]. In particular, inhibition of STAT3 may be very useful in combination with tyrosine kinase inhibitors, TKIs since redundancies in STAT3 activation have been linked to an acquired resistance to TKI-based therapies [2]. Thus, STAT3 is an important factor for cancer development, progression and in therapy resistance, and represents a valid target for therapy.

We are interested in defining mechanisms that govern the specificity of different biological effects in response to STAT3 activation. Such a specificity is likely mediated through a cooperation of STAT3 with different additional factors, such as chromatic remodeling proteins and transcription factors. We have previously studied inhibition of IL-6-induced STAT3 signaling in response to IFNa or Hsp90-inhibitors in multiple myeloma [3-5]. One of the current projects aims at identifying novel proteins involved in STAT3-mediated gene transcription by studying DNA-bound STAT3 interactome.

Development of small molecule inhibitors targeting STAT3 has been a great challenge [1]. We have performed a large scale screen and identified novel compounds that inhibit STAT3-dependent transcriptional activity using an in-house developed cell-based reporter assay [6]. From that screen, we have also selected and further optimized active electrophilic compounds that have not been previously described as STAT inhibitors. Using chemical and biological methods, we have identified their possible target, a protein regulating the RedOx state in cells whose inhibition leads to a formation of inactive STAT3 dimers and inhibition of STAT3-dependent transcription (S. Busker at al., Manuscript).

Resistance to anti-cancer therapy represents a major problem in cancer treatment. We study primary and acquired resistance to therapy using multicellular spheroids (MCS). We previously found that MCS induced a limited set of type I interferon- stimulated genes (ISGs), highly similar to a gene signature designated Interferon-related DNA Damage Signature (IRDS) [7]. Type I IFN-induced genes are normally regulated by the transcription complex ISGF3 consisting of pSTAT1, pSTAT2, and a DNA-binding adaptor protein IRF9. Interestingly, even un-phosphorylated ISFG3 complex (U-ISGF3) can induce a gene signature highly similar to the IRDS [8]. We found that IRF9 was critical for these genes’ induction in MCS and for the resistance of HCT116 colon cancer cell line to chemotherapeutic drugs [7]. More recently we identified STAT3 to be activated and induced in MCS upstream of IRF9 leading to the induction of ISG/ISGF3 expression [9]. STAT3 phosphorylation was dependent on gp130/JAK activity. The cytokine or GF and the mechanisms of gp130 engagement remain to be identified. We also plan to further develop the 3D culture system by co-culturing tumor and stroma cells, and to use these 3D cultures for combination drug therapy, including TKIs and compounds that inhibit STAT3 activity.

Collaborations

  • Chemical Biology Consortium, CBCS-KI, SciLife Lab, Solna.
  • J. Lehtiö, H. Johansson and B. Page, OncPat, KI and SciLife Lab, Solna.
  • E. Arnér, Department of Medical Biochemistry and Biophysics, Biomedicum
  • G. Stark, HJ. Cheong, Lerner research Institute, Cleveland Clinic, USA

References

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