Combined MEK and JAK/STAT3 pathway inhibition effectively decreases SHH medulloblastoma tumor progression.
Jamie ZagozewskiStephanie BorlaseBrent J GuppyLudivine Coudière-MorrisonGhazaleh M ShahriaryVictor GordonLisa LiangStephen ChengChristopher J PorterRhonda KelleyCynthia HawkinsJennifer A ChanYan LiangJingjing GongCarolina NörOlivier SaulnierRobert J Wechsler-ReyaVijay RamsawamiTamra E Werbowetski-OgilviePublished in: Communications biology (2022)
Medulloblastoma (MB) is the most common primary malignant pediatric brain cancer. We recently identified novel roles for the MEK/MAPK pathway in regulating human Sonic Hedgehog (SHH) MB tumorigenesis. The MEK inhibitor, selumetinib, decreased SHH MB growth while extending survival in mouse models. However, the treated mice ultimately succumbed to disease progression. Here, we perform RNA sequencing on selumetinib-treated orthotopic xenografts to identify molecular pathways that compensate for MEK inhibition specifically in vivo. Notably, the JAK/STAT3 pathway exhibits increased activation in selumetinib-treated tumors. The combination of selumetinib and the JAK/STAT3 pathway inhibitor, pacritinib, further reduces growth in two xenograft models and also enhances survival. Multiplex spatial profiling of proteins in drug-treated xenografts reveals shifted molecular dependencies and compensatory changes following combination drug treatment. Our study warrants further investigation into MEK and JAK/STAT3 inhibition as a novel combinatory therapeutic strategy for SHH MB.
Keyphrases
- pi k akt
- signaling pathway
- endothelial cells
- oxidative stress
- emergency department
- mouse model
- squamous cell carcinoma
- type diabetes
- cell proliferation
- papillary thyroid
- white matter
- multiple sclerosis
- resting state
- free survival
- insulin resistance
- functional connectivity
- skeletal muscle
- adverse drug
- brain injury
- subarachnoid hemorrhage
- pluripotent stem cells
- wild type
- cerebral ischemia