Resistance of tumor cells to therapy (2613)

the doc.dr.sc. Anamaria Brozović, Scientific Advisor

Ruđer Boskovic Institute

Understand the molecular mechanisms by which tumor cells become resistant to therapy, and the application of this basic knowledge in clinical treatment.

The sensitivity of tumor cells to therapy is determined by a number of parameters. They depend on the status of the cell itself (origin, degree of differentiation, changes in the genome and protein function...), and on the type of therapy, the chosen drug and the method of application.
We will present three basic groups of causes of resistance of tumor cells to therapy: a) resistance related to protective cell mechanisms, b) resistance associated with inhibition of apoptosis, c ) resistance related to cell adhesion for the ectracellular matrix, that is, to other cells.
In addition to a): Membrane transport proteins in the regulation of the intracellular amount of compounds. Glutathione and associated enzymes in the protection of cells from oxidative radicals, xenobiotics, and in maintaining the redox status of cells. Ways to repair damage caused by DNA. Nuclear enzymes topoisomerase. Adaptation to physical and chemical agents.
With b) The process of apoptosis. Signal's roads. p53, a family of Bcl-2 proteins, caspases, their inhibitors. NF-B. The role of apoptosis on resistance to therapy.
With c) Adhesion cell. Integrini, cadherins. Signaling pathways. Protein kinase B/Akt. GTPaze. Cell cytoskeleton. The role of intercellular connections and cell-extracellular matrix connections in resistance to therapy.
With each unit, the presentation of the application of basic research in the clinic.
Each chapter will be accompanied by new tumor treatment strategies based on new basic insights.

1. Explain the mechanism of resistance of tumor cells to therapy.
2. Analyze the molecular mechanisms of the resistance of tumor cells to therapy.
3. Propose molecular methods used in the investigation of molecular mechanisms of resistance of tumor cells to therapy.
4. Determine the meaning of molecular mechanisms of tumor cell resistance in a personalized approach to treating patients with tumours.

Follow-up of lectures, participation in exercises, seminar work

1. Molecular Biology of the Cell, 6th Edition, GS Garland Science, Taylot & Francis Group, New York, 2015.
2. Assaraf YG, Brozovic A, Gonçalves AC, Jurkovicova D, Linē A, Machuqueiro M, Saponara S, Sarmento-Ribeiro AB, Xavier CPR, Vasconcelos MH. The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resist Updat 2019; doi: 10.1016/j.drup.2019.100645.
3. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nature Rev Cancer 2013; 13:714-726.
4. Gottesman MM , Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporter. Review. Nature Rev 2002; 2: 48-58.
5. Zaheer U, Faheem M, Qadri I, Begum N, Yassine HM, Al Thani AA, Mathew S. Expression profile of MicroRNA: An Emerging Hallmark of Cancer. Curr Pharm Des 2019; 25:642-653.
6. Filomeni G, Rotilio G, Ciriolo MR. Cell signalling and the glutathione redox system. Biochem Pharmacol 2002; 64:1057-1064.
7. Christmann M, Kaina B. Epigenetic regulation of DNA repair genes and implications for tumor therapy. Mutat Res. 2019; 780:15-28.
8. D'Arcy MS. Cell death: a review of the major forms of apoptosis, necrosis and autophagy Cell Biol Int. 2019; 43(6):582-592.
9. Green DR, Llambi F.Cell Death Signaling. Cold Spring Harb Perspect Biol. 2015; 1:7(12).
10. Hamidi H, Pietilä M, Ivaska J. The complexity of integrins in cancer and new scopes for therapeutic targeting. Br J Cancer 2016; 115:1017-1023.

Supplementary (recommended) literature:
1. Ghosh S. Cisplatin: The first metal based anticancer drug. Bioorg Chem. 2019; 88: 102925
2. Brozovic A. The relationship between platinum drug resistance and epithelial-mesenchymal transition. Arch Toxicol. 2017; 91(2):605-619.
3. Brozovic A, Ambriović-Ristov A, Osmak M. The relationship between cisplatin-induced reactive oxygen species, glutathione, and BCL-2 and resistance to cisplatin. Crit Rev Toxicol. 2010; 40(4):347-59.
4. Brozovic A, Osmak M. Activation of mitogen-activated protein kinases by cisplatin and their role in cisplatin-resistance. Cancer Lett. 2007; 251(1):1-16.
5. Grootjans S, Vanden Berghe T, Vandenabeele P. Initiation and execution mechanisms of necroptosis: an overview. Cell Death Differ. 2017; 24:1184–95.
6. Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014; 15:49–63.
7. Dickens LS, Powley IR, Hughes MA, MacFarlane M. The 'complexities' of life and death: death receptor signalling platforms. Exp Cell Res. 2012; 318:1269–77.
8. Jost PJ, Grabow S, Gray D, McKenzie MD, Nachbur U, Huang DC, et al. XIAP discriminates between type I and type II FAS-induced apoptosis. It's Nature. 2009; 460:1035–9.
9. Lopez J, Tait SW. Mitochondrial apoptosis: killing cancer using the enemy within. No. J Cancer. 2015; 112:957–62.
10. Shani Bialik, Santosh K. Dasari, Adi Kimchi. Autophagy-dependent cell death – where, how and why a cell eats itself to death J Cell Sci 2018; 131: jcs215152

The success of the course will be evaluated annually by the joint expert committee of the Ruđer Boskovic Institute, the University of Dubrovnik and the University of Josip Juraj Strossmayer in Osijek based on exam success and surveys.