Borlase Stephanie, DeCarlo Alexandria, Coudière-Morrison Ludivine, Liang Lisa, Porter Christopher J, Ramaswamy Vijay, Werbowetski-Ogilvie Tamra E
Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Cell Death Discov. 2023 Sep 19;9(1):347. 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.
音猬因子（SHH）髓母细胞瘤（MBs）预后中等，且肿瘤间存在广泛的异质性。虽然SHH通路拮抗剂对青春期后的患者有效，但年轻患者会出现明显的副作用，并且下游SHH通路基因发生突变的肿瘤将产生耐药性。因此，需要新的靶向治疗方法。在此，我们对强效MEK抑制剂（MEKi）曲美替尼在2个人类和3个小鼠SHH MB模型中的肿瘤特性进行了临床前体外测试，并在3个原位MB异种移植模型中进行了体内测试。曲美替尼显著减小肿瘤球大小、降低干/祖细胞增殖、活力和迁移能力。对人类和小鼠经曲美替尼处理的细胞进行RNA测序证实了这些发现，细胞周期、干细胞通路和SHH通路相关基因的表达降低，同时与细胞死亡和纤毛病相关的基因表达增加。重要的是，曲美替尼在体内也能减少肿瘤生长并延长生存期。细胞周期相关的E2F靶基因集在曲美替尼处理的肿瘤球和原发性异种移植中均普遍下调的基因中显著富集。然而，IL6/JAK STAT3和TNFα/NFκB信号基因集在曲美替尼体内治疗后特异性上调，表明长期MEK抑制后存在代偿性分子变化。我们的研究揭示了曲美替尼在有效减弱SHH MB肿瘤进展中的新作用，有必要进一步研究这种强效MEK1/2抑制剂单独或与其他靶向治疗联合用于治疗MAPK通路活性升高的SHH MB。
