STAT3 as a target for anti-cancer therapy

The aim of this project is to study the mechanisms of STAT3-regulated transcription, its involvement in cancer progression/therapy resistance and developing small-molecule inhibitors of STAT3 transcriptional activity.

Although largely dispensable in normal adult somatic tissues, the transcription enhancer STAT3 is activated in a large variety of tumors down-stream of receptor- and non-receptor tyrosine kinases (TK), such as Src, c-Met, EGF-R, JAKs, stimulated by growth factors (GF) and cytokines. Phosphorylated STAT3 binds as a dimer to a specific DNA sequence in promoters to induce/enhance transcription of genes. An abnormal activation of STAT3 has been detected at a high frequency in many types of solid tumors, multiple myeloma and leukemia. STAT3 activation regulates a variety of processes such as proliferation, inhibition of apoptosis, epithelial-mesenchymal transition, tumor angiogenesis, and tumor-associated inflammation. STAT3 is also an important factor for maintenance of pluripotent mouse ES cells and of so called 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 both glioblastoma and breast cancer CSCs, and is among cytokines and GFs that govern stroma-tumor interaction. Thus, STAT3 is an important factor for cancer development and progression in a variety of cancer-associated processes, and the repertoire of target genes driven by STAT3 as well as its function are likely to cell type-specific [1, 2].

We are interested in defining what governs the specificity of different biological effects in response to STAT3 activation. This probably requires a differential gene repertoire and cooperation with different additional 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 is devoted to find novel proteins involved in STAT3-mediated gene transcription. Our approach is to identify DNA-bound STAT3 interactome using mass-spectrometry. The identification of the factors that cooperate with STAT3 is crucial to understand the role of STAT3 in cancer and for the development of targeted anti-cancer therapy.

STAT3 is a promising target for cancer therapy. In particular, STAT3 inhibitors maybe very useful in combination with TKIs. Since targeting up-stream TKs (such as EGFR) can inhibit STAT3 phosphorylation, redundancies in STAT3 activation have been linked to an acquired resistance to TK inhibitory therapies [6, 7]. 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 [8]. From that screen, we have selected 19 hit compounds containing a common core structure that has not been previously described as a STAT inhibitor. Using structural medicinal chemistry-based optimization, a panel of 40 compounds with IC50 activities as low as 70 nM have been synthesized. A number of carefully selected compounds are being currently assayed in a variety of chemical and biological studies for further characterization. They will be then tested in pharmacological assays for stability and selective activity.

Resistance to anti-cancer therapy represent a major problem in cancer treatment. We have approached this problem using multicellular spheroid (MCS) model system. We 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) [9]. Type I IFN-induced genes are normally regulated by the transcription complex ISGF3 consisting of phosphorylated STAT1 and STAT2, and a DNA-binding adaptor protein IRF9. However, even un-phosphorylated ISFG3 complex (U-ISGF3) can induce a gene signature very similar to the IRDS [10]. We found that IRF9 is absolutely critical for these genes’ induction and for the resistance of colon cancer cell lines to chemotherapeutic drugs [9]. STAT3 is also activated and induced in MCS and is known to be involved in therapy resistance. We are now studying the mechanisms of IRF9 induction, independently of IFNs, and involvement of STAT3 in this process.


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


1. STAT3-mediated autophagy dependence identifies subtypes of breast cancer where autophagy inhibition can be efficacious.
Maycotte P, Gearheart C, Barnard R, Aryal S, Mulcahy Levy J, Fosmire S, et al
Cancer Res. 2014 May;74(9):2579-90

2. The STATs of cancer--new molecular targets come of age.
Yu H, Jove R
Nat. Rev. Cancer 2004 Feb;4(2):97-105

3. An activated JAK/STAT3 pathway and CD45 expression are associated with sensitivity to Hsp90 inhibitors in multiple myeloma.
Lin H, Kolosenko I, Björklund A, Protsyuk D, Österborg A, Grandér D, et al
Exp. Cell Res. 2013 Mar;319(5):600-11

4. Interferon alpha induces cell death through interference with interleukin 6 signaling and inhibition of STAT3 activity.
Thyrell L, Arulampalam V, Hjortsberg L, Farnebo M, Grandér D, Pokrovskaja Tamm K
Exp. Cell Res. 2007 Nov;313(19):4015-24

5. IL-6 activated JAK/STAT3 pathway and sensitivity to Hsp90 inhibitors in multiple myeloma.
Kolosenko I, Grander D, Tamm K
Curr. Med. Chem. 2014 ;21(26):3042-7

6. Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia.
Eiring A, Page B, Kraft I, Mason C, Vellore N, Resetca D, et al
Leukemia 2015 Mar;29(3):586-597

7. Stat3-targeted therapies overcome the acquired resistance to vemurafenib in melanomas.
Liu F, Cao J, Wu J, Sullivan K, Shen J, Ryu B, et al
J. Invest. Dermatol. 2013 Aug;133(8):2041-9

8. Identification of novel small molecules that inhibit STAT3-dependent transcription and function.
Kolosenko I, Yu Y, Busker S, Dyczynski M, Liu J, Haraldsson M, et al
PLoS ONE 2017 ;12(6):e0178844

9. Cell crowding induces interferon regulatory factor 9, which confers resistance to chemotherapeutic drugs.
Kolosenko I, Fryknäs M, Forsberg S, Johnsson P, Cheon H, Holvey-Bates E, et al
Int. J. Cancer 2015 Feb;136(4):E51-61

10. IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage.
Cheon H, Holvey-Bates E, Schoggins J, Forster S, Hertzog P, Imanaka N, et al
EMBO J. 2013 Oct;32(20):2751-63