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Accession IconGSE69359

RAS/MAPK activation drives resistance to Smo inhibition, metastasis and tumor evolution in Shh pathway-dependent tumors

Organism Icon Mus musculus
Sample Icon 24 Downloadable Samples
Technology Badge Icon Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)

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Aberrant Shh signaling promotes tumor growth in diverse human cancers. The importance of Shh signaling is particularly evident in medulloblastoma and basal cell carcinoma (BCC), where inhibitors targeting the Shh pathway component Smoothened (Smo) show great therapeutic promise. However, the emergence of drug resistance limits long-term efficacy and the mechanisms of resistance remain poorly understood. Using new culturing techniques, we established a cohort of Shh pathway-driven medulloblastoma cell lines derived from Ptch+/- mice. Using this new model, we identify activation of the RAS/MAPK pathway circumvents Shh pathway-dependency, drives tumor growth and enhances metastatic behavior.Together these findings reveal a critical role of RAS/MAPK pathway in drug resistance and tumor evolution of Shh pathway-dependent tumors.
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