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

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13046-023-02682-5.

Related collections

Most cited references 50

Record: found
Abstract: found
Article: found

Hallmarks of Cancer: The Next Generation

Douglas Hanahan, Robert A. Weinberg (2011)

The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.

0 comments Cited 11467 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support.

Paul A. Harris, Robert Taylor, Robert Thielke … (2009)

Research electronic data capture (REDCap) is a novel workflow methodology and software solution designed for rapid development and deployment of electronic data capture tools to support clinical and translational research. We present: (1) a brief description of the REDCap metadata-driven software toolset; (2) detail concerning the capture and use of study-related metadata from scientific research teams; (3) measures of impact for REDCap; (4) details concerning a consortium network of domestic and international institutions collaborating on the project; and (5) strengths and limitations of the REDCap system. REDCap is currently supporting 286 translational research projects in a growing collaborative network including 27 active partner institutions.

0 comments Cited 9897 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Integrated Genomic Analyses of Ovarian Carcinoma

Nikolaus Schultz (2012)

Summary The Cancer Genome Atlas (TCGA) project has analyzed mRNA expression, miRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas (HGS-OvCa) and the DNA sequences of exons from coding genes in 316 of these tumors. These results show that HGS-OvCa is characterized by TP53 mutations in almost all tumors (96%); low prevalence but statistically recurrent somatic mutations in 9 additional genes including NF1, BRCA1, BRCA2, RB1, and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three miRNA subtypes, four promoter methylation subtypes, a transcriptional signature associated with survival duration and shed new light on the impact on survival of tumors with BRCA1/2 and CCNE1 aberrations. Pathway analyses suggested that homologous recombination is defective in about half of tumors, and that Notch and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.

0 comments Cited 1179 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Giovanni Scambia: giovanni.scambia@policlinicogemelli.it

Claudio Sette:

ORCID: http://orcid.org/0000-0003-2864-8266

claudio.sette@unicat.it

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J Exp Clin Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 18 May 2023

Publication date PMC-release: 18 May 2023

Publication date Collection: 2023

Volume: 42

Electronic Location Identifier: 126

Affiliations

[1 ]GRID grid.8142.f, ISNI 0000 0001 0941 3192, Department of Neuroscience, Section of Human Anatomy, , Catholic University of the Sacred Heart, ; 00168 Rome, Italy

[2 ]GRID grid.411075.6, ISNI 0000 0004 1760 4193, GSTeP Organoids Research Core Facility, , IRCCS Fondazione Policlinico A. Gemelli, ; 00168 Rome, Italy

[3 ]GRID grid.8142.f, ISNI 0000 0001 0941 3192, Department of Woman and Child Health and Public Health, , Catholic University of the Sacred Heart, ; 00168 Rome, Italy

[4 ]GRID grid.414603.4, 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

[5 ]GRID grid.411075.6, ISNI 0000 0004 1760 4193, Unit of Translational Medicine for Woman and Child Health, , IRCCS Fondazione Policlinico Universitario A. Gemelli, ; 00168 Rome, Italy

[6 ]GRID grid.414603.4, Department of Diagnostic and Laboratory Medicine, Unity of Chemistry, Biochemistry and Clinical Molecular Biology, , Fondazione Policlinico Universitario A. Gemelli IRCCS, ; Rome, Italy

[7 ]GRID grid.8142.f, ISNI 0000 0001 0941 3192, Department of Basic Biotechnological Sciences, , Intensive Care and Perioperative Clinics Research, Catholic University of the Sacred Heart, Università Cattolica del Sacro Cuore, ; Rome, Italy

[8 ]GRID grid.5390.f, ISNI 0000 0001 2113 062X, Department of Medical Area (DAME), , University of Udine, ; Udine, Italy

[9 ]GRID grid.411492.b, Clinic of Obstetrics and Gynecology, , “Santa Maria Della Misericordia” University Hospital, Azienda Sanitaria Universitaria Friuli Centrale, ; Udine, Italy

Author information

Claudio Sette http://orcid.org/0000-0003-2864-8266

Article

Publisher ID: 2682

DOI: 10.1186/s13046-023-02682-5

PMC ID: 10193743

PubMed ID: 36588153

SO-VID: 9771a229-5a2e-4eee-9f8a-4fa12a3e174b

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 21 February 2023

Date accepted : 21 April 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100005010, Associazione Italiana per la Ricerca sul Cancro;

Award ID: IG23416

Award Recipient : Claudio Sette

Funded by: FundRef http://dx.doi.org/10.13039/501100003196, Ministero della Salute;

Award ID: GR 2019-12371435

Award ID: Ricerca Corrente 2022

Award Recipient : Giuseppe Vizzielli Giovanni Scambia

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

Read this article at

Abstract

Background

Methods

Results

Conclusions

Supplementary Information

Related collections

Karger: Oncology

Most cited references 50

Hallmarks of Cancer: The Next Generation

Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support.

Integrated Genomic Analyses of Ovarian Carcinoma

Author and article information

Contributors

Journal

Affiliations

Author information

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 381

Cited by 3

Most referenced authors 922