| Autor: |
Drosos Y; Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), 15701 Athens, Greece., Konstantakou EG; Massachusetts General Hospital Cancer Center (MGHCC), Harvard Medical School, Boston, MA 02114, USA., Bassogianni AS; Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), 15701 Athens, Greece., Nikolakopoulos KS; Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), 15701 Athens, Greece., Koumoundourou DG; Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), 15701 Athens, Greece., Markaki SP; Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), 15701 Athens, Greece., Tsitsilonis OE; Section of Animal and Human Physiology, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), 15701 Athens, Greece., Voutsinas GE; Laboratory of Molecular Carcinogenesis and Rare Disease Genetics, Institute of Biosciences and Applications (IBA), National Center for Scientific Research (NCSR) 'Demokritos', 15310 Athens, Greece., Valakos D; Center of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 11527 Athens, Greece., Anastasiadou E; Center of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 11527 Athens, Greece., Thanos D; Center of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 11527 Athens, Greece., Velentzas AD; Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), 15701 Athens, Greece., Stravopodis DJ; Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens (NKUA), 15701 Athens, Greece. |
| Abstrakt: |
Bladder cancer (BLCA) is the sixth most common type of cancer and has a dismal prognosis if diagnosed late. To identify treatment options for BLCA, we systematically evaluated data from the Broad Institute DepMap project. We found that urothelial BLCA cell lines are among the most sensitive to microtubule assembly inhibition by paclitaxel treatment. Strikingly, we revealed that the top dependencies in BLCA cell lines include genes encoding proteins involved in microtubule assembly. This highlights the importance of microtubule network dynamics as a major vulnerability in human BLCA. In cancers such as ovarian and breast, where paclitaxel is the gold standard of care, resistance to paclitaxel treatment has been linked to p53-inactivating mutations. To study the response of BLCA to microtubule assembly inhibition and its mechanistic link with the mutational status of the p53 protein, we treated a collection of BLCA cell lines with a dose range of paclitaxel and performed a detailed characterization of the response. We discovered that BLCA cell lines are significantly sensitive to low concentrations of paclitaxel, independently of their p53 status. Paclitaxel induced a G2/M cell cycle arrest and growth inhibition, followed by robust activation of apoptosis. Most importantly, we revealed that paclitaxel triggered a robust DNA-damage response and apoptosis program without activating the p53 pathway. Integration of transcriptomics, epigenetic, and dependency data demonstrated that the response of BLCA to paclitaxel is independent of p53 mutational signatures but strongly depends on the expression of DNA repair genes. Our work highlights urothelial BLCA as an exceptional candidate for paclitaxel treatment. It paves the way for the rational use of a combination of paclitaxel and DNA repair inhibitors as an effective, novel therapeutic strategy. |
