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

Aug 21, 2023

Contributors: Consuelo Pitolli,Alberto Marini,Marika Guerra,Marco Pieraccioli,Veronica Marabitti,Fernando Palluzzi,Luciano Giacò,Gianpiero Tamburrini,Francesco Cecconi,Francesca Nazio,Claudio Sette,Vittoria Pagliarini

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.
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.
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.
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’.

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ABOUT THE CONTRIBUTORS

Consuelo Pitolli,Alberto Marini,Marika Guerra,Marco Pieraccioli,Veronica Marabitti,Fernando Palluzzi,Luciano Giacò,Gianpiero Tamburrini,Francesco Cecconi,Francesca Nazio,Claudio Sette,Vittoria Pagliarini
Consuelo Pitolli

Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy.

Alberto Marini

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.

Marika Guerra

Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy.

Marco Pieraccioli

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.

Veronica Marabitti

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.

Fernando Palluzzi

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.

Luciano Giacò

Bioinformatics Research Core Facility, Gemelli Science and Technology Park (GSTeP), IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168, Rome, Italy.

Gianpiero Tamburrini

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.

Francesco Cecconi

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.

Francesca Nazio

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.

Claudio Sette

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.

Vittoria Pagliarini

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.