ONGOING RESEARCH
Factors involved in DRUG RESISTANCE IN CANCER
We have involved several S6 kinases in the regulation of drug resistance in a variety of cancer types, including lung, breast cancer and sarcoma. Our current work aims to identify the downstream targets involved in this effect, including translation and mRNA splicing factors. Our goal is to propose novel therapeutic targets for cancer treatment and increase our understanding of the molecular mechanisms leading to cancer cell survival.
Proteins regulating the sensitivity of non small-cell lung cancer (NSCLC) to EGFR inhibitors
EGFR inhibitors, such as erlotinib and gefitinib, are new molecules used in the clinic to treat a proportion of lung cancer patients with EGFR activating mutations. However, these tumours ultimately become resistant to these compounds. We are part of a European FP7 consortium that aims both at understanding the various mechanisms responsible for this resistance and at designing novel therapeutic agents that may circumvent it.
cancer invasiveness and metastasis
We have performed a series of RNAi screens and identified novel regulators of lung and breast cancer cell migration and invasiveness. We are now in the process of investigating those proteins to understand their mechanism of action. In order to reach this goal, we have developed a series of in vitro and in vivo models to test novel agents that prevent cancer dissemination.
Compounds design/SCREENING/testing for our various targets
We are closely working with chemists, protein modellers and crystallographers to design novel compounds targeting our targets of interest. Through our industrial collaborations we also perform research using experimental compounds to assess their effect on lung cancer biology. Our clinical links enable us to take part in the design and running of clinical trials that aim at identifying novel therapies for lung cancer.
OUR LATEST PUBLISHED WORK
Finding new therapeutic targets for Mesothelioma
Our latest published research on the crosstalk between mesothelioma cells and fibroblasts and how this proposes novel therapeutic strategies for the disease can be found here: Chrisochoidou, Y 2023 Cell Death and Disease (2023) 14:725 ; https://doi.org/10.1038/s41419-023-06240-x
RSKs in cancer biology
Our latest work on the role of RSK4 in cancer is published in Science Translational Medicine (Chrysostomou, S. et al. 2021: Vol. 13, Issue 602, eaba4627; DOI: 10.1126/scitranslmed.aba4627)
Below is a talk that presents this work:
Targeting RSK4 prevents both chemoresistance and metastasis in lung and bladder cancer
Also, see our summary video:
Drug resistance in choriocarcinoma
We have published on how ATR and CDK4/6 can be targeted for therapeutic benefit in drug-resistant choriocarcinoma (Georgiou et al. 2022 Oncogene 41:2540–2554; https://doi.org/10.1038/s41388-022-02251-8)
and an associated conference talk can be found here.
S6K2 and downstream targets in the regulation of drug resistance
Below is a presentation on our past work on hnRNPA1 as a new mediator of the pro-survival effects of FGF2:
The RNA binding protein hnRNPA1 regulates cell death in response to FGF2
Collaborators
Prof William Cookson, Imperial College-NHLI, Mesothelioma research funded by the Mesothelioma Centre, 2017
Dr Paul Huang, Institute for Cancer Research (ICR), Proteomics and phosphorpoteomics analysis of cancer cells in response to molecular perturbations. Also, substrate fishing for novel mammalian kinase isoforms., 2017
Dr Paul Ajun, Dundee Cell, Phosphoproteomics of gestational trophoblastic disease drug resistance, 2013 - 2017
Dr Catherine Tralau-Stewart, Imperial College-London-UK, Drug Discovery, 2011
Dr Maruf Ali, Imperial College-London-UK, Crystallography, 2011
Prof Yulan Wang, Chinese Academy of Sciences-Wuhan-China, Metabonomics, 2011
Prof R Berkowitz, Dana Farber, Boston, USA, Gestational Trophoblastic Disease drug resistance, 2011 - 2014
Dr Miguel Martins, MRC-Leicester-UK, Apoptosis Research, 2011
Prof Lin Guo, Wuhan University-Wuhan-China, Quantitative Mass Spectrometry, 2010
Prof Johan Van Lint, Katholieke Universiteit Leuven-Leuven-Belgium, Mass Spectrometry, 2010
Dr Jeff Smaill, Auckland Cancer Society Research Centre, Synthesis and testing of FGFR inhibitor prodrugs, 2010
Etienne Waelkens, Katholieke Universiteit Leuven-Belgium, Mass Spectrometry, 2010
Dr Pieter Peeters, Johnson & Johnson-Beerse-Belgium, Drug Discovery, 2009
Dr Ines Royau, Janssen Pharmaceutica NV-Beerse-Belgium, Oncology Research, 2009
Prof Maggie Dallman, Imperial College-London-UK, Zebrafish research, 2009
Prof Mariano Barbacid, CNIO, Barcelona, Spain, role of S6K2 in lung cancer development using spontaneous murine lung cancer models, 2009 - 2014
Dr Alexandre Arcaro, University of Bern, Resistance of lung cancer cells to EGFR-TKIs and cell signalling, 2009 - 2014
Dr. Martin Holcik, CHEO Research Institute-University of Ottawa-Canada, Apoptosis Research, 2008
Dr Daniel Zicha, Cancer Research UK-London Research Institute-London-UK, Microscopy, 2006
Prof Julian Downward, Cancer Research UK-London Research Institute, Cell signalling in Cancer, 2006
Prof Ivan Gout, UCL-London-UK, Cell signalling, 2002
Guest Lectures
Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer, European Association for Cancer Research 2021 annual conference, 2021
The kinase RSK4 regulates drug resistance, metastasis and metabolic reprogramming in lung cancer, EACR A Matter of Life or Death Conference, Bergamo, Italy, 2020
The kinase RSK4 regulates drug resistance, metastasis and metabolic reprogramming in lung cancer, International E-Conference on Cancer Science and Therapy, 2020
hnRNPA1 phosphorylation and nucleocytoplasmic shuttling regulates IRES-driven mRNA translation, SPLICING 2020, 3rd International Caparica Conference in Splicing, Lisbon, Portugal, 2020
RSK4 and cellular metabolism in lung cancer, UCL Metabolic club, London, UK, 2019
The kinase RSK4 regulates drug resistance, metastasis and metabolic reprogramming in lung cancer, 15th International Conference on Cancer Science & Therapy, UK, 2019
The kinase RSK4 regulates drug resistance, metastasis and metabolic reprogramming in lung cancer, University of Poitiers, Poitiers, France, 2019
The kinase RSK4 regulates drug resistance, metastasis and metabolic reprogramming in lung cancer, 34th Euro-Global Summit on Cancer Therapy & Radiation Oncology, UK, 2019
Resistance to tyrosine kinase-targeted therapy in lung cancer: autophagy and metabolic changes, 27th World Oncologists Annual Conference, Chicago, USA, 2018
The kinase RSK4 regulates drug resistance, metastasis and metabolic reprogramming in lung cancer, Kyoto University Department of Oncology, Kyoto, Japan, 2018
The kinase RSK4 regulates drug resistance, metastasis and metabolic reprogramming in lung cancer, Tokyo Institute of Technology, Tokyo, Japan, 2018
Resistance to tyrosine kinase-targeted therapy in lung cancer: autophagy and metabolic changes, Cancer Research Therapy Conference 2018, UK, 2018
The kinase RSK4 regulates the metabolism of lung cancer cells, International Association for Cellular Coenzymes Symposium 2018, London, UK, 2018
Resistance to tyrosine kinase-targeted therapy in lung cancer: autophagy and metabolic changes, Biomarker Research in Clinical Medicine 2018, Paris, France, 2018
Resistance to tyrosine kinase-targeted therapy in lung cancer: autophagy and metabolic changes, Manchester Cancer Institute Retreat, UK, 2018
Resistance to tyrosine kinase-targeted therapy in lung cancer: autophagy and metabolic changes, Sheffield University, UK, 2018
S6 kinase 2 signalling regulates BCL-XL and XIAP translation through hnRNPA1, Genes and Cancer Meeting, Cambridge, UK, 2017
Signalling-driven hnRNPA1 nucleo-cytoplasmic cycling to promote selective translation, Translation UK 2017, University of Nottingham, Nottingham, UK, 2017
Glutathione metabolism and resistance of EGFR-T790M mutant lung cancer cells to erlotinib, Targeted Cancer Therapies, Bengaluru, India, 2017
Decreased glutathione synthesis mediates EGFR T790M-driven erlotinib resistance, World Cancer 2016 Conference, London, 2016
Decreased glutathione synthesis mediates EGFR T790M-driven erlotinib resistance, Future Horizons in Lung Cancer, Royal Society of Medicine, London, 2016
NRF2-mediated changes in glutathione metabolism mediate the resistance of EGFR-T790M mutant lung cancer cells to erlotinib, Personalized Medicine-2015, Valencia, 2015
FGF-2/S6K2 signalling promotes the nucleo-cytoplasmic shuttling of hnRNPA1 to increase cap-independent translation of BCL-XL and XIAP in cancer, Cancer Science-2015, Dubai, 2015
Metabonomics approach to identifying novel regulator of targeted therapy in lung cancer, Chinese Academy of Sciences, Wuhan, China, 2014
Changes in glutathione metabolism mediate the resistance of EGFRT790M mutant lung cancer cells to erlotinib., Symposium on metabonomics on translational medicine, Shanghai, China, 2014
RSKs in lung cancer invasion and metastasis, BIT 4th annual congress of Molecular and Cell Biology, Dalian, China, 2014
Studying cell invasiveness using complex 2D and 3D culture assays and zebrafish models., High-content screening conference, Sheffield University, Sheffield, UK, 2014
Changes in glutathione metabolism mediate the resistance of EGFRT790M mutant lung cancer cells to erlotinib, NCRI Conference, Liverpool, UK, 2013
Studying cell invasiveness using complex 2D and 3D culture assays and zebrafish models, SMI 3D culture Conference, London, 2013
Studying cell invasiveness using complex 2D and 3D culture assays and zebrafish models, Cell Based Assay Conference, London, 2013
FGF-2/S6K2 and hnRNPA1in the translational regulation of Bcl-XL and XIAP, Indian Association of Cancer Research, New Dehli, 2013
FGF-2/S6K2 and hnRNPA1in the translational regulation of Bcl-XL and XIAP, Genes and Cancer conference, Warwick, UK., 2012
RSKs in lung and bladder cancer biology, 18th UK Academic Screening Group meeting. MRC-NIMR, London, UK, 2012
FGF-2/S6K2 and hnRNPA1in the translational regulation of Bcl-XL and XIAP, MRC, Leicester, UK, 2012
Studying cell invasiveness using complex 3D culture assays and zebrafish models, Syngenta, Berlin, 2012
S6 Kinases in lung cancer biology, WIPM, Chinese Academy of Sciences, Wuhan, China, 2011
Identification of novel modulators of lung cancer cell motility and invasiveness, RNAi & High Content Imaging Symposium 2011, Oxford-UK, 2011
S6 Kinases in Lung Cancer, Wuhan University, Wuhan-China, 2011
Using High Content Screening for the identification of novel modulators of cell migration and invasion in lung cancer, Cell-based Assay Conference, Cologne, Germany, 2010
High-throughput screening for the identification of novel modulators of cell migration, invasion and cytoskeletal organisation in lung cancer, Molecular Devices Technical Conference, Winersh Triangle-UK, 2010
S6 kinase 2 (S6K2) regulates cell survival through modulation of protein translation and mRNA splicing, RSM/BACR Meeting on MicroRNA and Translational Regulation in Cancer, London-UK, 2009
RNAi-mediated screen for regulators of cell migration and invasion in lung cancer, University of North Carolina, Chapel Hill, US, 2009
RNAi-mediated screen for regulators of cell migration and invasion in lung cancer, Jansen Pharmaceuticals, Beerse-Belgium, 2009
S6 kinases in the chemoresistance and metastasis of lung cancer, Wuhan School of Medicine, Wuhan, China, 2009
S6 kinase 2 and FGF-2 in lung cancer cell survival, Wuhan University, Wuhan, China, 2009
RNAi-mediated screen for regulators of cell migration and invasion in lung cancer, High-Throughput User Conference, Düsseldorf, Germany, 2009
RSK family members in the regulation of lung cancer cell migration and invasion, St Bart’s and Queen Mary’s Medical School, London-UK, 2008
The FGFR inhibitor PD173074 blocks SCLC growth in vitro and in vivo, National Cancer Research Institute Meeting, Birmingham, UK, 2008
The use of RNAi-based kinome library screening in the identification of potential therapeutic targets for cancer, CNRS/INSERM Molecular Biology Department-Poitiers University, Poitiers, France, 2005
Role of the PKC/B-Raf/S6K2 multiprotein complex in FGF-2-mediated survival, Cancer Research UK, Charterhouse Square, London, UK, 2004
Fibroblast growth factor-2 induces translational regulation of Bcl-XL and Bcl-2 via a MEK dependent pathway: correlation with resistance to etoposide induced apoptosis, BCRM, Leeds, UK, 2001
Towards a clinical trial ofHsp65 gene therapy for malignant mesothelioma, British Thoracic Society Winter Meeting, London, UK, 1998
Gene therapy for malignant mesothelioma with a heat shock protein 65 gene, ALA/ATS International Conference, Chicago, USA, 1998
Research Staff
Roy,R
Research Student Supervision
Akçakaya,P
Alcantara,D
Alkaf,B, hnRNPA1 as an AKT substrate
Barnes,E, RPS6KC1 in lung cancer cel migration and invasion
Castle,J, Using Zebrafish as a high-throughput drug screening tool in cancer therapeutics
Chater,E, EGFR TKI resistance mechanisms and metabonomics
Chater,E, EGFR TKI resistance mechanisms and metabonomics
Chiao Chin Gao,, RSK4 metabolomics in lung cancer
Choo,J, Metothrexate resistance in gestational trophoblastic disease
Cooney,D, Identification of small compound inhibitors of Ribosomal S6 Kinase 4 (RSK4)
Eckert,A, RSK4 drug discovery
GEORGIOU,M, Identification of small compound inhibitors of RSK4
Gan,CC, Metabolic signature and transforming potential associated with mycoplasma infection of lung epithelial cells
Georgiou,M, GTD drug resistance mechanisms
Gubbins,J, Bone metastasis in Prostate Cancer
Huang,P, Role of MARK4 in lung cancer cell metastasis, immune response and development in zebrafish
Huang,Y, RSK4 drug screening
Huang,Y, The use of nanofiber/microfiber scaffolds for developing 3D cancer cell models
Huang,Y, RSK4 drug screening
Huang,Y, Metabolic signature and transforming potential associated with mycoplasma infection of lung epithelial cells
Huang,Y, FGF2/S6K2/hnRNPA1 pathway in sarcoma
Kalu,S, Metabolic changes accompanying the overexpression of RSK4 in lung cancer
Lara,R, PhD project-siRNA screening for modulators of lung cancer cells motility and invasiveness
Lau,C, Investigating changes in EGFR signaling as a result of Erlotinib resistance
Li,M, S6K2 drug discovery
Liang,H-C, FGF10 in breast cancer
METCALF,G, The role of MARK4 in lung cancer invasiveness
Majka,G
McLachlan,S, Elucidating the role of hnRNPA1 in lung cancer drug resistance
Metcalf,G, RPS6KC1 in lung cancer metastasis
Moonamale,D, RSK4 expression in cancer
Moonamale,D, Role of RSK4 in promoting metastasis, invasion and chemoresistance in model cancer cells.
Morcuende Ventura,V, RPS6KC1 in lung cancer
Mufti,U, PhD project: Screening & Identification of Kinases Involved in Drug Resistance in Bladder Cancer
Munro,C, PhD project: Drugable genome-wide study of lung cancer cell local invasion towards the endothelium
Protopapa,L, The cell cycle pathway to methotrexate resistant choriocarcinoma
RIBEZZO,F, Studying the mechanisms of bone metastasis in prostate cancer
Rupniewska,E, PhD project: Targeting SRC family kinases in lung cancer
SARPER,M
Sormendi,S, Biological function of S6K2-S3
Spain,G, RSK4 and metabolic changes in lung cancer
Sum Yee,J, Modelling and Monitoring Cancer Cell Invasiveness using Zebrafish as an Animal Model
Tsimon,M
Veal,M, Investigating the role of p90 Ribosomal S6 kinase 4 in regulation of cellular energy metabolism in Lung Cancer cells
Venmann,E, Cloning, expression, purification and crystallisation studies of RSK4 in parallel with a bioinformatics approach towards understanding the structure of RSK4
Walsh,D, RSK4 in lung cancer metabonomics
Xue,M, Identification of S6K2/PKCeps protein/protein interaction inhibitors
Zhang,A, FGF10 in the growth of breast cancer cells
Zhang,W, Elucidating the role of hnRNPA1 in lung cancer drug resistance