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

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

  • J Exp Clin Cancer Res. 2023 Aug 21;42(1):214. doi: 10.1186/s13046-023-02790-2.
Consuelo Pitolli 1,  Alberto Marini 1 2,  Marika Guerra 1,  Marco Pieraccioli 1 2,  Veronica Marabitti 3 4,  Fernando Palluzzi 5 6,  Luciano Giacò 5,  Gianpiero Tamburrini 1 7,  Francesco Cecconi 3 8 9,  Francesca Nazio 3 4,  Claudio Sette 10 11,  Vittoria Pagliarini 12 13
Affiliations

Affiliations

  • 1 Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy.
  • 2 GSTEP-Organoids Research Core Facility, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168, Rome, Italy.
  • 3 Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  • 4 Department of Biology, University of Rome Tor Vergata, Rome, Italy.
  • 5 Bioinformatics Research Core Facility, Gemelli Science and Technology Park (GSTeP), IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168, Rome, Italy.
  • 6 Present Address: Integrated Omics Department, Novo Nordisk, 2860, Søborg, Denmark.
  • 7 Pediatric Neurosurgery, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168, Rome, Italy.
  • 8 Department of Basic Biotechnological Sciences, Intensive Care and Perioperative Clinics Research, Catholic University of the Sacred Heart, 00168, Rome, Italy.
  • 9 Unit of Cell Stress and Survival, Danish Cancer Society Research Center, Copenhagen, Denmark.
  • 10 Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy. [email protected].
  • 11 GSTEP-Organoids Research Core Facility, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168, Rome, Italy. [email protected].
  • 12 Department of Neuroscience, Section of Human Anatomy, Catholic University of the Sacred Heart, 00168, Rome, Italy. [email protected].
  • 13 GSTEP-Organoids Research Core Facility, IRCCS Fondazione Policlinico Universitario Agostino Gemelli, 00168, Rome, Italy. [email protected].
PMID: 37599362 DOI: 10.1186/s13046-023-02790-2
Abstract

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.

Keywords

Brain tumors; Chemotherapy resistance; RNA polymerase processivity; RNA processing regulation; THZ531.

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