Institute for Cancer Research
Department of Medicine I
Medical University of Vienna
A-1090 Vienna, Austria
The main focus of the Szakacs lab is membrane transport biology, in particular ABC transporters responsible for the multidrug resistance phenotype of cancer cells. In the past years we have developed a new concept to target the Achilles’ heel of resistant cancer cells (ERC Stg 2012-2016). Our current work is based on mouse models of cancer and 3D cell culturing to study clinically relevant mechanisms enabling the survival cancer cells despite toxic chemotherapy.
Development of MDR-selective compounds to prevent, revert and eliminate multidrug resistance in cancer. One of the best characterized mechanisms of multidrug resistance (MDR) is based on drug efflux mediated by ABC transporters, in particular P-glycoprotein (P-gp)1. To date, attempts to target MDR have been unsuccessful2. In a recently completed ERC project we developed compounds with robust MDR-selective toxicity, established their mechanism of action, and demonstrated their in vivo applicability3. Based on these results we hypothesize that P-gp represents a paradoxical vulnerability that can be targeted to combat MDR cancer4,5. In this project we will use a genetically engineered mouse model (GEMM) of breast cancer to target P-gp mediated MDR6. Acquired resistance of tumor-bearing GEMMs and GEMM-derived orthotopic transplants will be induced by chemotherapy7. Tumors grown from drug-sensitive and multidrug resistant primary murine organoid cultures8 engineered to express fluorescent marker proteins will be treated with MDR-selective protocols. Genome-wide DNA/histone methylation analyses and chromatin accessibility assays (with GE) will be used to map epigenetic changes associated with the rapid P-gp loss induced by MDR-selective compounds. The potential of epigenetic drugs to re-sensitize MDR tumors will be tested using drug resistant organoids. This experimental toolkit will allow the study of the evolutionary fitness cost of drug resistance9 and the evaluation of the potential of the MDR-selective compounds to prevent, revert or eliminate resistance.
(1) Robey, R. W.; Pluchino, K. M.; Hall, M. D.; Fojo, A. T.; Bates, S. E.; Gottesman, M. M. Revisiting the Role of ABC Transporters in Multidrug-Resistant Cancer. Nat. Rev. Cancer 2018, 1. doi.org/10.1038/s41568-018-0005-8.
(2) Szakacs, G.; Paterson, J. K.; Ludwig, J. A.; Booth-Genthe, C.; Gottesman, M. M. Targeting Multidrug Resistance in Cancer. Nat Rev Drug Discov 2006, 5 (3), 219–234.
(3) SZAKÁCS, G.; SOÓS, T.; FERENCZI-PALKÓ, R.; FÜREDI, A.; TÓTH, S.; TÜRK, D.; Pape, V.; FÜLÖP, F.; SZATMÁRI, I.; Dormán, G.; et al. Mdr-Reversing 8-Hydroxy-Quinoline Derivatives, Patent Pending (WO 2017175018 A2), April 5, 2017.
(4) Füredi, A.; Tóth, S.; Szebényi, K.; Pape, V. F. S.; Türk, D.; Kucsma, N.; Cervenák, L.; Tóvári, J.; Szakács, G. Identification and Validation of Compounds Selectively Killing Resistant Cancer: Delineating Cell Line Specific Effects from P-Glycoprotein-Induced Toxicity. Mol. Cancer Ther. 2016, molcanther.0333.2016. doi.org/10.1158/1535-7163.MCT-16-0333-T.
(5) Szakács, G.; Hall, M. D.; Gottesman, M. M.; Boumendjel, A.; Kachadourian, R.; Day, B. J.; Baubichon-Cortay, H.; Di Pietro, A. Targeting the Achilles Heel of Multidrug-Resistant Cancer by Exploiting the Fitness Cost of Resistance. Chem. Rev. 2014, 114 (11), 5753–5774. doi.org/10.1021/cr4006236.
(6) Rottenberg, S.; Borst, P. Drug Resistance in the Mouse Cancer Clinic. Drug Resist. Updat. 2012, 15 (1–2), 81–89. doi.org/10.1016/j.drup.2012.01.001.
(7) Füredi, A.; Szebényi, K.; Tóth, S.; Cserepes, M.; Hámori, L.; Nagy, V.; Karai, E.; Vajdovich, P.; Imre, T.; Szabó, P.; et al. Pegylated Liposomal Formulation of Doxorubicin Overcomes Drug Resistance in a Genetically Engineered Mouse Model of Breast Cancer. J. Controlled Release 2017, 261, 287–296. doi.org/10.1016/j.jconrel.2017.07.010.
(8) Duarte, A. A.; Gogola, E.; Sachs, N.; Barazas, M.; Annunziato, S.; Ruiter, J. R. de; Velds, A.; Blatter, S.; Houthuijzen, J. M.; van de Ven, M.; et al. BRCA-Deficient Mouse Mammary Tumor Organoids to Study Cancer-Drug Resistance. Nat. Methods 2018, 15 (2), 134–140. doi.org/10.1038/nmeth.4535.
(9) SZYBALSKI, W. Genetic Studies on Microbial Cross Resistance to Toxic Agents. IV. Cross Resistance of Bacillus Megaterium to Forty-Four Antimicrobial Drugs. Appl. Microbiol. 1954, 2 (2), 57–63.
1. Füredi, A., S. Tóth, K. Szebényi, V. F. S. Pape, D. Türk, N. Kucsma, L. Cervenak, J. Tóvári, and G. Szakács. 2017. Identification and Validation of Compounds Selectively Killing Resistant Cancer: Delineating Cell Line–Specific Effects from P-Glycoprotein–Induced Toxicity. Mol. Cancer Ther. 16: 45–56. doi: 10.1158/1535-7163.MCT-16-0333-T.
2. Füredi, A., K. Szebényi, S. Tóth, M. Cserepes, L. Hámori, V. Nagy, E. Karai, P. Vajdovich, T. Imre, P. Szabó, D. Szüts, J. Tóvári, and G. Szakács. 2017. Pegylated liposomal formulation of doxorubicin overcomes drug resistance in a genetically engineered mouse model of breast cancer. J. Controlled Release 261: 287–296. doi.org/10.1016/j.jconrel.2017.07.010
3. Szakács, G., M. D. Hall, M. M. Gottesman, A. Boumendjel, R. Kachadourian, B. J. Day, H. Baubichon-Cortay, and A. Di Pietro. 2014. Targeting the Achilles Heel of Multidrug-Resistant Cancer by Exploiting the Fitness Cost of Resistance. Chem. Rev. 114: 5753–5774. doi: 10.1021/cr4006236
4. Szakacs, G., J. K. Paterson, J. A. Ludwig, C. Booth-Genthe, and M. M. Gottesman. 2006. Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5: 219–34. doi: 10.1158/0008-5472.CAN-09-2422.
5. Szakács, G., J.-P. Annereau, S. Lababidi, U. Shankavaram, A. Arciello, K. J. Bussey, W. Reinhold, Y. Guo, G. D. Kruh, M. Reimers, J. N. Weinstein, and M. M. Gottesman. 2004. Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell 6: 129–137. DOI:10.1016/j.ccr.2004.06.026