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

• Published in: Cell death discovery Vol. 9; no. 1; p. 347
• Main Authors: Borlase, Stephanie, DeCarlo, Alexandria, Coudière-Morrison, Ludivine, Liang, Lisa, Porter, Christopher J., Ramaswamy, Vijay, Werbowetski-Ogilvie, Tamra E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.09.2023; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/67/1922; 631/67/2332; Animal models; Antagonists; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell cycle; Cell Cycle Analysis; Cell death; Cell migration; Cell proliferation; Cell size; Cell survival; Drug resistance; E2F protein; Genes; Hedgehog protein; Life Sciences; MAP kinase; Medical prognosis; Medulloblastoma; MEK inhibitors; NF-κB protein; Progenitor cells; Stat3 protein; Stem Cells; Tumors; Xenografts
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-023-01646-0

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.