Dual inhibition of CDK12 and CDK13 uncovers actionable vulnerabilities in patient-derived ovarian cancer organoids.

Autor: Cesari E; Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy.; GSTeP Organoids Research Core Facility, IRCCS Fondazione Policlinico A. Gemelli, 00168, Rome, Italy., Ciucci A; GSTeP Organoids Research Core Facility, IRCCS Fondazione Policlinico A. Gemelli, 00168, Rome, Italy.; Department of Woman and Child Health and Public Health, Catholic University of the Sacred Heart, 00168, Rome, Italy., Pieraccioli M; Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy.; GSTeP Organoids Research Core Facility, IRCCS Fondazione Policlinico A. Gemelli, 00168, Rome, Italy., Caggiano C; Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy.; GSTeP Organoids Research Core Facility, IRCCS Fondazione Policlinico A. Gemelli, 00168, Rome, Italy., Nero C; Department of Woman and Child Health and Public Health, Catholic University of the Sacred Heart, 00168, Rome, Italy.; Department of Woman and Child Health and Public Health, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Francesco Vito 1, 00168, Rome, Italy., Bonvissuto D; Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy., Sillano F; Department of Woman and Child Health and Public Health, Catholic University of the Sacred Heart, 00168, Rome, Italy., Buttarelli M; Department of Woman and Child Health and Public Health, Catholic University of the Sacred Heart, 00168, Rome, Italy.; Unit of Translational Medicine for Woman and Child Health, IRCCS Fondazione Policlinico Universitario A. Gemelli, 00168, Rome, Italy., Piermattei A; Department of Woman and Child Health and Public Health, Catholic University of the Sacred Heart, 00168, Rome, Italy., Loverro M; Department of Woman and Child Health and Public Health, Catholic University of the Sacred Heart, 00168, Rome, Italy.; Department of Woman and Child Health and Public Health, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Francesco Vito 1, 00168, Rome, Italy., Camarda F; Department of Woman and Child Health and Public Health, Catholic University of the Sacred Heart, 00168, Rome, Italy.; Department of Woman and Child Health and Public Health, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Francesco Vito 1, 00168, Rome, Italy., Greco V; Department of Diagnostic and Laboratory Medicine, Unity of Chemistry, Biochemistry and Clinical Molecular Biology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.; Department of Basic Biotechnological Sciences, Intensive Care and Perioperative Clinics Research, Catholic University of the Sacred Heart, Università Cattolica del Sacro Cuore, Rome, Italy., De Bonis M; Department of Basic Biotechnological Sciences, Intensive Care and Perioperative Clinics Research, Catholic University of the Sacred Heart, Università Cattolica del Sacro Cuore, Rome, Italy., Minucci A; Department of Basic Biotechnological Sciences, Intensive Care and Perioperative Clinics Research, Catholic University of the Sacred Heart, Università Cattolica del Sacro Cuore, Rome, Italy., Gallo D; Department of Woman and Child Health and Public Health, Catholic University of the Sacred Heart, 00168, Rome, Italy.; Unit of Translational Medicine for Woman and Child Health, IRCCS Fondazione Policlinico Universitario A. Gemelli, 00168, Rome, Italy., Urbani A; Department of Diagnostic and Laboratory Medicine, Unity of Chemistry, Biochemistry and Clinical Molecular Biology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.; Department of Basic Biotechnological Sciences, Intensive Care and Perioperative Clinics Research, Catholic University of the Sacred Heart, Università Cattolica del Sacro Cuore, Rome, Italy., Vizzielli G; Department of Medical Area (DAME), University of Udine, Udine, Italy.; Clinic of Obstetrics and Gynecology, 'Santa Maria Della Misericordia' University Hospital, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy., Scambia G; Department of Woman and Child Health and Public Health, Catholic University of the Sacred Heart, 00168, Rome, Italy. giovanni.scambia@policlinicogemelli.it.; Department of Woman and Child Health and Public Health, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Francesco Vito 1, 00168, Rome, Italy. giovanni.scambia@policlinicogemelli.it., Sette C; Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy. claudio.sette@unicat.it.; GSTeP Organoids Research Core Facility, IRCCS Fondazione Policlinico A. Gemelli, 00168, Rome, Italy. claudio.sette@unicat.it.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2023 May 18; Vol. 42 (1), pp. 126. Date of Electronic Publication: 2023 May 18.
DOI: 10.1186/s13046-023-02682-5
Abstrakt: Background: High grade serous ovarian cancer (HGSOC) is highly lethal, partly due to chemotherapy resistance and limited availability of targeted approaches. Cyclin dependent kinases 12 and 13 (CDK12/13) are promising therapeutic targets in human cancers, including HGSOC. Nevertheless, the effects of their inhibition in HGSOC and the potential synergy with other drugs are poorly known.
Methods: We analyzed the effects of the CDK12/13 inhibitor THZ531 in HGSOC cells and patient-derived organoids (PDOs). RNA sequencing and quantitative PCR analyses were performed to identify the genome-wide effects of short-term CDK12/13 inhibition on the transcriptome of HGSOC cells. Viability assays with HGSOC cells and PDOs were performed to assess the efficacy of THZ531 as single agent or in combination with clinically relevant drugs.
Results: The CDK12 and CDK13 genes are deregulated in HGSOC and their concomitant up-regulation with the oncogene MYC predicts poor prognosis. HGSOC cells and PDOs display high sensitivity to CDK12/13 inhibition, which synergizes with drugs in clinical use for HGSOC. Transcriptome analyses revealed cancer-relevant genes whose expression is repressed by dual CDK12/13 inhibition through impaired splicing. Combined treatment with THZ531 and inhibitors of pathways regulated by these cancer relevant genes (EGFR, RPTOR, ATRIP) exerted synergic effects on HGSOC PDO viability.
Conclusions: CDK12 and CDK13 represent valuable therapeutic targets for HGSOC. We uncovered a wide spectrum of CDK12/13 targets as potential therapeutic vulnerabilities for HGSOC. Moreover, our study indicates that CDK12/13 inhibition enhances the efficacy of approved drugs that are already in use for HGSOC or other human cancers.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje