MYC up-regulation confers vulnerability to dual inhibition of CDK12 and CDK13 in high-risk Group 3 medulloblastoma.

Autor: Pitolli C; Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy., Marini A; Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy.; GSTEP-Organoids Research Core Facility, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168, Rome, Italy., Guerra M; Department of Neuroscience, Section of Human Anatomy, 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 Universitario Agostino Gemelli, 00168, Rome, Italy., Marabitti V; Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.; Department of Biology, University of Rome Tor Vergata, Rome, Italy., Palluzzi F; Bioinformatics Research Core Facility, Gemelli Science and Technology Park (GSTeP), IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168, Rome, Italy.; Present Address: Integrated Omics Department, Novo Nordisk, 2860, Søborg, Denmark., Giacò L; Bioinformatics Research Core Facility, Gemelli Science and Technology Park (GSTeP), IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168, Rome, Italy., Tamburrini G; Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy.; Pediatric Neurosurgery, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168, Rome, Italy., Cecconi F; Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.; Department of Basic Biotechnological Sciences, Intensive Care and Perioperative Clinics Research, Catholic University of the Sacred Heart, 00168, Rome, Italy.; Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen, Denmark., Nazio F; Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.; Department of Biology, University of Rome Tor Vergata, Rome, Italy., Sette C; Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy. claudio.sette@unicatt.it.; GSTEP-Organoids Research Core Facility, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168, Rome, Italy. claudio.sette@unicatt.it., Pagliarini V; Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy. vittoria.pagliarini@unicatt.it.; GSTEP-Organoids Research Core Facility, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168, Rome, Italy. vittoria.pagliarini@unicatt.it.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2023 Aug 21; Vol. 42 (1), pp. 214. Date of Electronic Publication: 2023 Aug 21.
DOI: 10.1186/s13046-023-02790-2
Abstrakt: Background: Medulloblastoma (MB) is the most common cerebellar malignancy during childhood. Among MB, MYC-amplified Group 3 tumors display the worst prognosis. MYC is an oncogenic transcription factor currently thought to be undruggable. Nevertheless, targeting MYC-dependent processes (i.e. transcription and RNA processing regulation) represents a promising approach.
Methods: We have tested the sensitivity of MYC-driven Group 3 MB cells to a pool of transcription and splicing inhibitors that display a wide spectrum of targets. Among them, we focus on THZ531, an inhibitor of the transcriptional cyclin-dependent kinases (CDK) 12 and 13. High-throughput RNA-sequencing analyses followed by bioinformatics and functional analyses were carried out to elucidate the molecular mechanism(s) underlying the susceptibility of Group 3 MB to CDK12/13 chemical inhibition. Data from International Cancer Genome Consortium (ICGC) and other public databases were mined to evaluate the functional relevance of the cellular pathway/s affected by the treatment with THZ531 in Group 3 MB patients.
Results: We found that pharmacological inhibition of CDK12/13 is highly selective for MYC-high Group 3 MB cells with respect to MYC-low MB cells. We identified a subset of genes enriched in functional terms related to the DNA damage response (DDR) that are up-regulated in Group 3 MB and repressed by CDK12/13 inhibition. Accordingly, MYC- and CDK12/13-dependent higher expression of DDR genes in Group 3 MB cells limits the toxic effects of endogenous DNA lesions in these cells. More importantly, chemical inhibition of CDK12/13 impaired the DDR and induced irreparable DNA damage exclusively in MYC-high Group 3 MB cells. The augmented sensitivity of MYC-high MB cells to CDK12/13 inhibition relies on the higher elongation rate of the RNA polymerase II in DDR genes. Lastly, combined treatments with THZ531 and DNA damage-inducing agents synergically suppressed viability of MYC-high Group 3 MB cells.
Conclusions: Our study demonstrates that CDK12/13 activity represents an exploitable vulnerability in MYC-high Group 3 MB and may pave the ground for new therapeutic approaches for this high-risk brain tumor.
(© 2023. Italian National Cancer Institute ‘Regina Elena’.)
Databáze: MEDLINE
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