2. Academic Validation
  3. Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression

Cross-species analysis of SHH medulloblastoma models reveals significant inhibitory effects of trametinib on tumor progression

  • Cell Death Discov. 2023 Sep 19;9(1):347. doi: 10.1038/s41420-023-01646-0.
Stephanie Borlase 1,  Alexandria DeCarlo 2 3 4,  Ludivine Coudière-Morrison 1,  Lisa Liang 1,  Christopher J Porter 5,  Vijay Ramaswamy 2 3 4 6,  Tamra E Werbowetski-Ogilvie 7 8 9
Affiliations

Affiliations

  • 1 Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
  • 2 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • 3 The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
  • 4 Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
  • 5 Ottawa Bioinformatics Core Facility, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
  • 6 Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
  • 7 Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. Tamra.Ogilvie@bcm.edu.
  • 8 Texas Children's Hospital, Houston, TX, USA. Tamra.Ogilvie@bcm.edu.
  • 9 Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA. Tamra.Ogilvie@bcm.edu.
PMID: 37726268 DOI: 10.1038/s41420-023-01646-0
Abstract

Sonic Hedgehog (SHH) medulloblastomas (MBs) exhibit an intermediate prognosis and extensive intertumoral heterogeneity. While SHH pathway antagonists are effective in post-pubertal patients, younger patients exhibit significant side effects, and tumors that harbor mutations in downstream SHH pathway genes will be drug resistant. Thus, novel targeted therapies are needed. Here, we performed preclinical testing of the potent MEK Inhibitor (MEKi) trametinib on tumor properties across 2 human and 3 mouse SHH MB models in vitro and in 3 orthotopic MB xenograft models in vivo. Trametinib significantly reduces tumorsphere size, stem/progenitor cell proliferation, viability, and migration. RNA-sequencing on human and mouse trametinib treated cells corroborated these findings with decreased expression of cell cycle, stem cell pathways and SHH-pathway related genes concomitant with increases in genes associated with cell death and ciliopathies. Importantly, trametinib also decreases tumor growth and increases survival in vivo. Cell cycle related E2F target gene sets are significantly enriched for genes that are commonly downregulated in both trametinib treated tumorspheres and primary xenografts. However, IL6/JAK STAT3 and TNFα/NFκB signaling gene sets are specifically upregulated following trametinib treatment in vivo indicative of compensatory molecular changes following long-term MEK inhibition. Our study reveals a novel role for trametinib in effectively attenuating SHH MB tumor progression and warrants further investigation of this potent MEK1/2 inhibitor either alone or in combination with Other targeted therapies for the treatment of SHH MB exhibiting elevated MAPK pathway activity.

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