| Abstract [eng] |
Tumor resistance to chemotherapy drugs limits the efficiency of cancer treatment and remains a major problem in recurrent cancer therapy. Recent studies of resistant cancers show the growing complexity and emergence of cancer stem cells in the tumor environment, tumor cell heterogeneity and plasticity. All these processes are frequently linked with changes in response to genotoxic damage, prosurvival signaling, and dysfunctional cell death. Here, we investigated the two most prevalent breast and colorectal cancer tumor types. We used a triple-negative breast cancer cell line MDA-MB-231 as a model system for the study of resistance to experimental RH1 drug. Analysis of the RH1-resistant cell line revealed that the enrichment of cancer stem cells which are often associated with resistance and cancer renewal. Moreover, the activation of the c-KIT-AKT-mTOR signaling axis is crucial for the expansion of the CSC-like population. Therefore, inhibition of the c-KIT receptor along with RH1 can prevent resistance development. As a model system for colorectal cancer, we used colorectal carcinoma cell line HCT116 made resistant to widely used chemotherapy drugs, 5-fluorouracil (5-FU) and oxaliplatin (Oxa). In the case of 5-FU resistance, we showed changes in 5-FU metabolism proteins resulting in diminished DNA damage response. Whereas the resistance mechanism to Oxa was more complex and emphasized the importance of cancer cell plasticity through the enrichment of partial EMT phenotype bearing cells. Moreover, Oxa-resistant cells had an inactivating p53 mutations rendering Oxa treatment even more ineffective. This highlights the importance of mutational analysis of tumor suppressor genes and oncogenes before the selection of treatment. |
