Efekti inhibicije CXCR4 receptora i fokalne adhezione kinaze u supresiji invazije i prevazilaženju rezistencije kod nesitnoćelijskog karcinoma pluća
Effects of CXCR4 receptor and focal adhesion kinase inhibition in suppressing invasion and overcoming drug resistance in non-small cell lung carcinoma
Doctoral thesis (Published version)
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Lung cancer is the most commonly diagnosed type of malignant tumor and the leading cause of cancer death. Based on clinical prognosis and terapy response, up to 85% of lung cancer is clasified as non-small cell lung carcinoma (NSCLC). Although NSCLC is less agresive than small cell lung carcinoma (SCLC), its response to terapy is worse then SCLC. Two major causes of terapy failure of NSCLC with classic chemotherapeutics are the development of metastasis and chemotherapy resistance. Among other signaling molecules, CXCR4 receptor and focal adhesion kinase (FAK) are known to regulate these processes and their targeted inhibition represents a promising approach in the treatment of NSCLC. The aim of this study was to examine the role of CXCR4 and FAK in the invasiveness and resistance of NSCLC, as well as the potential of their inhibition in the suppression of invasion and the reversal of resistance in this type of lung carcinoma. In order to examine the role of CXCR4 and FAK in the invasiveness of NSCLC, in vitro system of cancer cell lines with different functional status of the p53 and PTEN tumor suppressors was established, as well as in vivo orthoptic metastatic model of NSCLC with p53/PTEN deficient tumors. The simultaneous inactivation of p53 and PTEN tumor suppressors in in vitro system lead to significant increase in invasive and migratory potential associated with activation of CXCR4 and FAK molecules and their downstream signaling molecules, AKT and ERK. The potential for supressing invasion and migration of p53-/PTEN- NSCLC cells, as well as the metastatic spread of aggressive p53/PTEN deficient tumors in in vivo model, has been shown by the application of specific inhibitors of CXCR4 and FAK, PF-573228 and WZ811. Furthermore, resistant cell lines NCI-H460/R and COR-L23 were used to investigate the role of CXCR4 and FAK in the development of NSCLC resistance to chemotherapy. NCI-H460/R and COR-L23 cells are characterized by an increased expression of ABCB1 and ABCC1 transporters, respectively. Our results additionally indicate that inhibition of CXCR4 and FAK in combination with DOX successfully sensitized NSCLC cells to the aforementioned cytostatic. By examining the mechanism of sensitization of NSCLC cells to DOX, it has been discovered that combined treatments reduced phosphorylation of FAK and AKT and lead to activation of senescence. Simultaneously with sensitization of cells to DOX, combined treatment successfully suppressed the invasion of resistant cells. Considering that resistance to therapy and metastasis are the two most important problems in NSCLC treatment, the results of the study show that targeted inhibition of CXCR4 and FAK, as well as their combination with standard chemotherapeutics, could be a promising therapeutic approach in the treatment of this disease.
Keywords:CXCR4; FAK; p53; PTEN; Invasion; Doxorubicin; Resistance; ABCB1; BACC1; Non-small cell lung carcinoma
Source:University of Belgrade, Faculty of Biology, 2018, 1-145
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