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Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma
Open accessAbstract
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.
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The structure and function of G-protein-coupled receptors
Rosenbaum, D. M., Rasmussen, S. G. F., & Kobilka, B. K. (2009) · Nature · doi:10.1038/nature08144 · Cited by 2,534
Altered Neural Cell Fates and Medulloblastoma in Mouse patched Mutants
Goodrich, L. V., Milenković, L., Higgins, K. M., & Scott, M. P. (1997) · Science · doi:10.1126/science.277.5329.1109 · Cited by 1,696
Cited by
Molecular subgroups of medulloblastoma: the current consensus
Taylor, M. D., Northcott, P. A., Korshunov, A., Remke, M., Cho, Y.-J., Clifford, S. C., Eberhart, C. G., Parsons, D. W., Rutkowski, S., Gajjar, A., et al. (2012) · Acta Neuropathologica · doi:10.1007/s00401-011-0922-z · Cited by 1,936
Robinson, G. W., Orr, B. A., Wu, G., Gururangan, S., Lin, T., Qaddoumi, I., Packer, R. J., Goldman, S., Prados, M. D., Desjardins, A., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.60.1591 · Cited by 448
Targeting HIF1α Eliminates Cancer Stem Cells in Hematological Malignancies
Wang, Y., Liu, Y., Malek, S. N., Zheng, P., & Liu, Y. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.02.006 · Cited by 410
“In contrast, resistance to an inhibitor of the Hedgehog pathway appears to develop readily due to mutation of Smoothened (Yauch et al., 2009).”
Beauchamp, E. M., Ringer, L., Bulut, G., Sajwan, K. P., Hall, M. D., Lee, Y.-C., Peaceman, D., Özdemirli, M., Rodriguez, O., Macdonald, T. J., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci42874 · Cited by 351
Kim, J., Aftab, B. T., Tang, J. Y., Kim, D., Lee, A. H., Rezaee, M., Kim, J., Chen, B., King, E. M., Borodovsky, A., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2012.11.017 · Cited by 346
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Metadata
- Authors
- Yauch, R. L., Dijkgraaf, G. J. P., Alicke, B., Januario, T., Ahn, C. P., Holcomb, T., Pujara, K., Stinson, J., Callahan, C. A., Tang, T., Bazan, J. F., Kan, Z., Seshagiri, S., Hann, C. L., Gould, S. E., Low, J. A., Rudin, C. M., & de Sauvage, F. J.
- Venue
- Science
- Published
- 2009-10-23
- Volume
- 326
- Issue
- 5952
- Pages
- 572-574
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1963493384
- Cited by
- 839
- References
- 2
- FWCI
- 26.53
- Type
- journal article
- Language
- en
- Open access
- green
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- Yauch, R. L., Dijkgraaf, G. J. P., Alicke, B., Januario, T., Ahn, C. P., Holcomb, T., Pujara, K., Stinson, J., Callahan, C. A., Tang, T., Bazan, J. F., Kan, Z., Seshagiri, S., Hann, C. L., Gould, S. E., Low, J. A., Rudin, C. M., & de Sauvage, F. J. (2009). Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma. Science. https://doi.org/10.1126/science.1179386
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
