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Combined MEK and JAK/STAT3 pathway inhibition effectively decreases SHH medulloblastoma tumor progression

14 juil. 2022Communications Biology

DOI : 10.1038/s42003-022-03654-9

Auteurs

Jamie Zagozewski, Stephanie Borlase, Brent J. Guppy, Ludivine Coudière-Morrison, Ghazaleh M. Shahriary, Victor Gordon, Lisa Liang, Stephen Cheng, Christopher J. Porter, Rhonda Kelley, Cynthia Hawkins, Jennifer A. Chan, Yan Liang, Jingjing Gong, Carolina Nör, Olivier Saulnier, Robert J. Wechsler-Reya, Vijay Ramaswamy, Tamra E. Werbowetski-Ogilvie

Résumé

Abstract

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.