发明名称 |
Mutant smoothened and methods of using the same |
摘要 |
The emergence of mutations in tyrosine kinases following treatment of cancer patients with molecular-targeted therapy represents a major mechanism of acquired drug resistance. Here, we describe a mutation in the serpentine receptor, Smoothened (SMO), which results in resistance to a Hedgehog (Hh) pathway inhibitor in medulloblastoma. A single amino acid substitution in a conserved aspartic acid residue of SMO maintains Hh signaling, but results in the inability of the Hh pathway inhibitor, GDC-0449, to bind SMO and suppress the pathway. This mutation was not only acquired in a GDC-0449-resistant mouse model of medulloblastoma, but was identified in a medulloblastoma patient following relapse on GDC-0449. The invention provides screening methods to detect SMO mutations and methods to screen for drugs that specifically modulate mutant SMO exhibiting drug resistance. |
申请公布号 |
AU2010289400(A1) |
申请公布日期 |
2012.04.12 |
申请号 |
AU20100289400 |
申请日期 |
2010.09.02 |
申请人 |
CURIS, INC.;GENENTECH, INC. |
发明人 |
DE SAUVAGE, FREDERIC J.;DIJKGRAAF, GERRIT J. P.;JANUARIO, THOMAS;YAUCH, ROBERT L. |
分类号 |
C07K14/705 |
主分类号 |
C07K14/705 |
代理机构 |
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代理人 |
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主权项 |
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地址 |
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