Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma

Abstract

A Smooth(ened) Path to Drug Resistance The Hedgehog (Hh) signaling pathway has emerged as a key contributor to the growth of medulloblastoma, an aggressive brain tumor. GDC-0449, a drug that ramps down this signaling pathway by binding to the Hh pathway component Smoothened, was recently shown to induce rapid and dramatic tumor regression in a patient with metastatic medulloblastoma, but the tumor eventually developed resistance to the drug. Yauch et al. (p. 572 , published online 3 September) show that resistance arose because the tumor acquired a mutation in Smoothened that disrupts binding of the drug. Identification of this resistance mechanism may facilitate the design of next-generation drugs for this type of cancer.