Novel targeted therapies in cancer to overcome drug resistance – Katja Pokrovskaja Tamm's Team

The goal is to find novel molecular markers and therapeutic approaches to overcome primary and secondary resistance and enable for individualized anti-cancer therapy. We focus specifically on autophagy, a cellular program activated as a survival mechanism in cancer cells and cancer stem cells, and also by many anticancer drugs during treatment. We use drug re-purposing and novel selective compounds targeting autophagy and lysosomal proteins in pre-clinical in vitro and ex vivo studies.

Our research

The aim of our research is to find novel therapeutic approaches to overcome primary and secondary resistance to anti-cancer therapy. Anti-cancer treatment often activates cellular protective mechanisms leading to an acquired resistance. One of them is induction of autophagy, which can protect cancer cells from stress and cytotoxic effects of drugs. Targeting autophagy for anti-cancer therapy using novel compounds against a lipid kinase Vps34 developed by several companies including Sprint Bioscience, is our strategy. In mouse studies, these compounds are shown to activate chemokine secretion and to reprogram cold into hot inflamed tumors improving the anti-PD-1/PD-L1 immunotherapy. Our goal is to reveal the mechanisms behind and to develop novel combination treatments using these compounds. STAT3 activation can also underlie resistance to therapy, such as multicellular drug resistance or to the tyrosine kinase inhibitors, and we are using novel approaches that we have developed for targeting STAT3. There is a cross-talk between autophagy and STAT3 pathway that we also explore, in particular, to eliminate resistant to treatment cancer stem cells. In collaboration with Mats Heyman and Anna Nilsson at KBH, we support a large sample collection of live-frozen cells purified from bone marrow and peripheral blood of pediatric patients with acute lymphocytic leukemia, ALL. Our goal is to identify novel biomarkers and novel targets for therapy in specific genetic sub-groups of ALL with a focus on pre-clinical validation of targeting autophagy and lysosomal pathway. We collaborate with Brinton Seashore-Ludlow, Tom Erkers and Rozbeh Jafari at SciLifeLab Solna, Martin Enge and Andreas Lundqvist at BioClinicum and Sprint Bioscience, Huddinge.


  • Swedish Cancer Society (STAT3 and autophagy as targets for therapy in pediatric acute leukemia)
  • Stiftelsen för Internationellt Onkologiskt Samarbete (Targeting Autophagy as a therapeutic strategy in pediatric acute lymphoblastic leukemia)
  • The Cancer Society in Stockholm (Targeting STAT3 and autophagy in pediatric acute leukemia)
  • Karolinska Institutet's research funds (Novel targeted therapy in acute leukemia)


Selected publications

Autophagy in anti-cancer therapy

The conserved cellular program of autophagy regulating protein and organelle turnover is important for cancer cell survival and also plays a role in the resistance to anti-cancer therapy. Autophagy is activated as a survival strategy in response to starvation and many types of stress. Anti-cancer therapy including radio- and chemo-therapy and tyrosine kinase inhibitors (TKI)-based therapy also induce autophagy. The impact of autophagy induction on a cell largely depends on a stimulus and a cell type [1, 2]. Generally, autophagy is believed to limit the cytotoxic effects of many drugs. We have found among 350 anti-cancer drugs about 100 drugs to modulate autophagy including TKIs erlotinib and sunitinib, in a phenotypic screen-based assay [3]. We characterized a novel potent small molecule Vps34 inhibitor that has been developed by Sprint Bioscience and used it to potentiate the cytotoxic effects of each of these drugs in breast cancer cell lines [3]. Together with Sprint Bioscience, we are now establishing the mRNA and protein expression profile of the breast cancer cell lines after inhibition of Vps34 to obtain prominent biomarkers for both the activity and the inhibition of autophagy in tumors. We also study the effects of autophagy inhibition on the tumor microenvironment using co-culture experiments and syngeneic mouse xenograft models.


  • Sprint Bioscience, NOVUM, Huddinge
  • CBCS - Chemical Biology Consortium, KI and SciLife
  • K. Wennerberg, FIMM, Finland.
  • The COST European autophagy network.


Inhibition of Vps34 reprograms cold into hot inflamed tumors and improves anti-PD-1/PD-L1 immunotherapy.
Noman MZ, Parpal S, Van Moer K, Xiao M, Yu Y, Viklund J, et al
Sci Adv 2020 May;6(18):eaax7881

Targeting autophagy by small molecule inhibitors of vacuolar protein sorting 34 (Vps34) improves the sensitivity of breast cancer cells to Sunitinib.
Dyczynski M, Yu Y, Otrocka M, Parpal S, Braga T, Henley AB, et al
Cancer Lett. 2018 10;435():32-43


Molecular mechanisms underlying pediatric leukemia development and treatment

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Yearly about 70-90 new ALL cases are diagnosed in Sweden and the incidence peaks at 2-5 years of age. It is characterized by an expansion of immature B or T lymphocytes. The disease is heterogeneous and the subtypes are further divided into more than 10 different genetic subgroups characterized by recurring genetic abnormalities that include chromosomal translocations, gene amplifications, and mutations. These, however, are insufficient to fully explain ALL pathogenesis as they fail to induce leukemia in in vivo models indicating that additional yet uncovered factors are involved.

We support a large sample collection of live-frozen cells purified from bone marrow and peripheral blood of pediatric patients with acute leukemia (under Stockholm Medical Biobank) and use this material in accordance with the ethical permits to study mechanisms of development and resistance to therapy in ALL and AML.

Our goal is to improve our understanding of the molecular mechanisms underlying development of ALL and to identify novel biomarkers and novel targets for therapy. Using primary samples, we focus on the large-scale RNA and protein analysis of the molecular landscape of ALL. This data will allow identifying signatures of different signalling pathways in the various genomic sub-groups of ALL. Two of the pathways will be specifically in focus: STAT3 and autophagy; their activity may serve as a biomarker for the use of targeting drugs against these pathways that we are developing.

Relapsed ALL is commonly associated with a highly resistant disease and a poor prognosis. The clones at relapse may be pre-existing in the diagnostic sample. These are leukemia initiating cells, stem-like cells, distinct from proliferating leukemic blasts, first discovered in AML. They are not so well-defined but are not readily eliminated by therapy. M. Enge’s group at OncPat study this heterogeneity within the leukemic cell population by single-cell sequencing of diagnostic vs. relapsed samples from the same individual. Using specific characteristics or biomarkers, such as cell surface markers, would allow sorting out these cells from the bulk of ALL cells at diagnosis and study the activity and role of the pathways of our interest, such as STAT3 and autophagy.

One of the key drugs in the treatment of pediatric ALL, glucocorticoid (GC) dexamethasone (Dex), induces apoptotic cell death of ALL cells. We found that prior apoptosis an extensive autophagy was induced. Interestingly, Dex profoundly affect leukemic cell energy metabolism by inhibiting glucose uptake and utilization. However, data suggested that inhibition of glucose metabolism per se will not activate autophagy or cell death in these cells. By assessing the global metabolic and protein changes induced by Dex, we found several pathways to be largely affected including glutamine synthesis and lysosomal function. These metabolic features modulated by Dex in leukemic cells may be responsible for the resistance to the GC-treatment in ALL.


  • Mats Heyman at The Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children’s Hospital.
  • R. Nilsson, CMM, Bioclinicum, KI
  • J. Lehtiö, M. Westerlund and R. Jafari, OncPat, KI and SciLife
  • M. Enge and V. Zachariadis, OncPat, Bioclinicum, KI

STAT3 as a target in anti-cancer therapy

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.


  • 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


1.Strategies and Approaches of Targeting STAT3 for Cancer Treatment.
Furtek SL, Backos DS, Matheson CJ, Reigan P
ACS Chem. Biol. 2016 Feb;11(2):308-18

2. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells.
Lee HJ, Zhuang G, Cao Y, Du P, Kim HJ, Settleman J
Cancer Cell 2014 Aug;26(2):207-21

3. An activated JAK/STAT3 pathway and CD45 expression are associated with sensitivity to Hsp90 inhibitors in multiple myeloma.
Lin H, Kolosenko I, Björklund AC, 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 KP
Curr. Med. Chem. 2014 ;21(26):3042-7

6. 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

7. 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 EG, et al
Int. J. Cancer 2015 Feb;136(4):E51-61

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

9. STAT3 is activated in multicellular spheroids of colon carcinoma cells and mediates expression of IRF9 and interferon stimulated genes.
Edsbäcker E, Serviss JT, Kolosenko I, Palm-Apergi C, De Milito A, Tamm KP
Sci Rep 2019 Jan;9(1):536