Latest Publications

@article{drapela_pre-existing_2024,

title = {Pre-existing cell subpopulations in primary prostate cancer tumors display surface fingerprints of docetaxel-resistant cells.},

author = {Stanislav Drápela and Barbora Kvokačková and Eva Slabáková and Anna Kotrbová and Kristína Gömöryová and Radek Fedr and Daniela Kurfürstová and Martin Eliáš and Vladimír Jr Študent and Frederika Lenčéšová and Ganji Sri Ranjani and Vendula Pospíchalová and Vítězslav Bryja and Wytske M. Weerden and Martin Puhr and Zoran Culig and Jan Bouchal and Karel Souček},

doi = {10.1007/s13402-024-00982-2},

issn = {2211-3436 2211-3428},

year  = {2024},

date = {2024-08-01},

journal = {Cellular oncology (Dordrecht, Netherlands)},

abstract = {PURPOSE: Docetaxel resistance is a significant obstacle in the treatment of prostate cancer (PCa), resulting in unfavorable patient prognoses. Intratumoral heterogeneity, often associated with epithelial-to-mesenchymal transition (EMT), has previously emerged as a phenomenon that facilitates adaptation to various stimuli, thus promoting cancer cell diversity and eventually resistance to chemotherapy, including docetaxel. Hence, understanding intratumoral heterogeneity is essential for better patient prognosis and the development of personalized treatment strategies. METHODS: To address this, we employed a high-throughput single-cell flow cytometry approach to identify a specific surface fingerprint associated with docetaxel-resistance in PCa cells and complemented it with proteomic analysis of extracellular vesicles. We further validated selected antigens using docetaxel-resistant patient-derived xenografts in vivo and probed primary PCa specimens to interrogate of their surface fingerprint. RESULTS: Our approaches revealed a 6-molecule surface fingerprint linked to docetaxel resistance in primary PCa specimens. We observed consistent overexpression of CD95 (FAS/APO-1), and SSEA-4 surface antigens in both in vitro and in vivo docetaxel-resistant models, which was also observed in a cell subpopulation of primary PCa tumors exhibiting EMT features. Furthermore, CD95, along with the essential enzymes involved in SSEA-4 synthesis, ST3GAL1, and ST3GAL2, displayed a significant increase in patients with PCa undergoing docetaxel-based therapy, correlating with poor survival outcomes. CONCLUSION: In summary, we demonstrate that the identified 6-molecule surface fingerprint associated with docetaxel resistance pre-exists in a subpopulation of primary PCa tumors before docetaxel treatment. Thus, this fingerprint warrants further validation as a promising predictive tool for docetaxel resistance in PCa patients prior to therapy initiation.},

note = {Place: Netherlands},

keywords = {CD95/Fas, Docetaxel resistance, Intratumoral heterogeneity, Plasticity, Prostate cancer, SSEA-4},

pubstate = {published},

tppubtype = {article}

}

@article{drapela_chk1_2020,

title = {The CHK1 inhibitor MU380 significantly increases the sensitivity of human docetaxel-resistant prostate cancer cells to gemcitabine through the induction of mitotic catastrophe.},

author = {Stanislav Drápela and Prashant Khirsariya and Wytske M. Weerden and Radek Fedr and Tereza Suchánková and Diana Búzová and Jan Červený and Aleš Hampl and Martin Puhr and William R. Watson and Zoran Culig and Lumír Krejčí and Kamil Paruch and Karel Souček},

doi = {10.1002/1878-0261.12756},

issn = {1878-0261 1574-7891},

year  = {2020},

date = {2020-10-01},

journal = {Molecular oncology},

volume = {14},

number = {10},

pages = {2487–2503},

abstract = {As treatment options for patients with incurable metastatic castration-resistant prostate cancer (mCRPC) are considerably limited, novel effective therapeutic options are needed. Checkpoint kinase 1 (CHK1) is a highly conserved protein kinase implicated in the DNA damage response (DDR) pathway that prevents the accumulation of DNA damage and controls regular genome duplication. CHK1 has been associated with prostate cancer (PCa) induction, progression, and lethality; hence, CHK1 inhibitors SCH900776 (also known as MK-8776) and the more effective SCH900776 analog MU380 may have clinical applications in the therapy of PCa. Synergistic induction of DNA damage with CHK1 inhibition represents a promising therapeutic approach that has been tested in many types of malignancies, but not in chemoresistant mCRPC. Here, we report that such therapeutic approach may be exploited using the synergistic action of the antimetabolite gemcitabine (GEM) and CHK1 inhibitors SCH900776 and MU380 in docetaxel-resistant (DR) mCRPC. Given the results, both CHK1 inhibitors significantly potentiated the sensitivity to GEM in a panel of chemo-naïve and matched DR PCa cell lines under 2D conditions. MU380 exhibited a stronger synergistic effect with GEM than clinical candidate SCH900776. MU380 alone or in combination with GEM significantly reduced spheroid size and increased apoptosis in all patient-derived xenograft 3D cultures, with a higher impact in DR models. Combined treatment induced premature mitosis from G1 phase resulting in the mitotic catastrophe as a prestage of apoptosis. Finally, treatment by MU380 alone, or in combination with GEM, significantly inhibited tumor growth of both PC339-DOC and PC346C-DOC xenograft models in mice. Taken together, our data suggest that metabolically robust and selective CHK1 inhibitor MU380 can bypass docetaxel resistance and improve the effectiveness of GEM in DR mCRPC models. This approach might allow for dose reduction of GEM and thereby minimize undesired toxicity and may represent a therapeutic option for patients with incurable DR mCRPC.},

note = {Place: United States},

keywords = {*Mitosis/drug effects, Animals, castration-resistant prostate cancer, Cell Death/drug effects, Cell Line, Cell Proliferation/drug effects, Checkpoint Kinase 1, Checkpoint Kinase 1/*antagonists & inhibitors/metabolism, Deoxycytidine/*analogs & derivatives/pharmacology, Docetaxel resistance, Docetaxel/*pharmacology, Drug resistance, gemcitabine, Humans, Male, Mice, mitotic catastrophe, MU380, Neoplasm/*drug effects, Piperidines/chemistry/*pharmacology, Prostatic Neoplasms/*pathology, Pyrazoles/chemistry/*pharmacology, Pyrimidines/chemistry/*pharmacology, S Phase/drug effects, SCID, Tumor, Xenograft Model Antitumor Assays},

pubstate = {published},

tppubtype = {article}

}