AI Article Synopsis
- Smoothened (SMO) inhibitors are being tested for treating sonic-hedgehog-driven medulloblastoma (SHH-MB), but patient responses vary widely.
- A study sequenced 133 SHH-MB cases, finding that PTCH1 mutations were common across all ages, while SUFU mutations primarily appeared in infants and adults had more SMO mutations.
- Functional tests showed tumors with PTCH1 mutations responded to SMO inhibitors, but those with SUFU mutations or MYCN amplifications were mostly resistant.
Article Abstract
Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4493053 | PMC |
| http://dx.doi.org/10.1016/j.ccr.2014.02.004 | DOI Listing |
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