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Sci. Signal., 27 October 2009
Vol. 2, Issue 94, p. ec348
[DOI: 10.1126/scisignal.294ec348]

EDITORS' CHOICE

Medicine A Smooth(ened) Path to Drug Resistance

Paula A. Kiberstis

Science, AAAS, Washington, DC 20005, USA

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. 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.

R. L. Yauch, G. J. P. Dijkgraaf, B. Alicke, T. Januario, C. P. Ahn, T. Holcomb, K. Pujara, J. Stinson, C. A. Callahan, T. Tang, J. F. Bazan, Z. Kan, S. Seshagiri, C. L. Hann, S. E. Gould, J. A. Low, C. M. Rudin, F. J. de Sauvage, Smoothened mutation confers resistance to a hedgehog pathway inhibitor in medulloblastoma. Science 326, 572–574 (2009). [Abstract] [Full Text]

Citation: P. A. Kiberstis, A Smooth(ened) Path to Drug Resistance. Sci. Signal. 2, ec348 (2009).


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