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 |
US2012282259(A1) |
申请公布日期 |
2012.11.08 |
申请号 |
US201013394069 |
申请日期 |
2010.09.02 |
申请人 |
DE SAUVAGE FREDERIC J.;DIJKGRAAF GERRIT J.P.;JANUARIO THOMAS;YAUCH ROBERT L.;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;A61K31/167;A61K31/4545;A61K31/496;A61K39/395;A61P35/00;C07H21/04;C07K16/30;C12N15/12;C12Q1/68;G01N21/76;G01N33/566 |
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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