5th Central and Eastern European Proteomic Conference

Cancer cell resistance to AURK-directed therapy: implications for anti-cancer strategies

Rita Hrabáková1, Madhu Kollareddy2, Kateřina Mairychová1, Petr Halada3, Marián Hajdúch2, Hana Kovářová1
1 Institute of Animal Physiology and Genetics, AS CR, v.v.i., Department of Reproductive and Developmental Biology, Libechov, Czech Republic;
2 Institute of Molecular and Translational Medicine, Laboratory of Experimental Medicine, Palacky University and University Hospital in Olomouc, Faculty of Medicine and Dentistry, Olomouc, Czech Republic;
3 Institute of Microbiology, AS CR, v.v.i., Laboratory of Molecular Structure Characterisation, Prague, Czech Republic

Colorectal cancer is the second leading cause of cancer-related deaths in the developed countries. Despite considerable success of combination treatments consisting of chemotherapy and targeted agents such as monoclonal antibodies and small molecular inhibitors, the prognosis often remains poor due to the development of drug resistance. The aim of the experimental work was to determine which mechanisms contribute to the development of the drug resistance in response of cancer cells to anti-cancer drugs.

In the present study, resistance toward Aurora kinase (AURK) inhibitors is being investigated in p53 wild-type and p53 null isogenic HCT116 cell lines. To allow the establishment of resistant clones, these cell lines were exposed to a toxic dose of AURK inhibitors for a few weeks. Comparative two-dimensional electrophoresis (pH 4-7 and 6-11, 10% SDS-PAGE) followed by MALDI-TOF/TOF identification revealed 82 differences in protein expression between sensitive and resistant cells. Follow up analysis by Western blot confirmed altered expression of several proteins in HCT116 resistant cells. The relative levels of such proteins have been further measured in the cells resistant to different anti-cancer drugs and the proteins associated with multidrug resistance were identified. Only some of these proteins with different functionality have been previously linked to the drug resistance. However, the identity of new candidates was demonstrated and the clarificatin of their emerging roles is under scrutiny in our laboratory.

We acknowledge support from the Czech Ministry of School and Education (LC07017) and Institutional Research Concepts AV0Z50450515 (IAPG) and AV0Z50200510 (IMIC).