Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma.
Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma.
复制标题
DOI：
10.1016/j.ccell.2015.02.001
复制
发表时间：
2015-03-09
期刊：
影响因子：
50.3
通讯作者：
de Sauvage FJ
中科院分区：
文献类型：
--
作者：
Sharpe HJ;Pau G;Dijkgraaf GJ;Basset-Seguin N;Modrusan Z;Januario T;Tsui V;Durham AB;Dlugosz AA;Haverty PM;Bourgon R;Tang JY;Sarin KY;Dirix L;Fisher DC;Rudin CM;Sofen H;Migden MR;Yauch RL;de Sauvage FJ
Smoothened （SMO）抑制剂正在临床研究中，用于治疗几种癌症。Vismodegib被批准用于局部晚期和转移性基底细胞癌（BCC）的治疗。大多数BCC患者对vismodegib有显著的临床获益，然而，一些患者产生耐药性。肿瘤活检的基因组分析显示，vismodegib耐药与Hedgehog （Hh）通路的再激活有关，主要是通过药物靶点SMO的突变，以及SUFU和GLI2拷贝数的同时变化。SMO突变要么直接损害药物结合，要么不同程度地激活SMO。此外，我们发现了肿瘤内异质性的证据，表明需要针对Hh通路多个水平的成分的联合治疗来克服耐药性。
Smoothened (SMO) inhibitors are under clinical investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). Most BCC patients experience significant clinical benefit on vismodegib, however, some develop resistance. Genomic analysis of tumor biopsies revealed vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
14.8
作者：
Nedelcu, Daniel;Liu, Jing;Xu, Yangqing;Jao, Cindy;Salic, Adrian
通讯作者：
Salic, Adrian
影响因子：
4.8
作者：
Gether, U;Ballesteros, JA;Kobilka, BK
通讯作者：
Kobilka, BK
DOI：
10.1126/science.1233009
发表时间：
2013-03-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Clark VE;Erson-Omay EZ;Serin A;Yin J;Cotney J;Ozduman K;Avşar T;Li J;Murray PB;Henegariu O;Yilmaz S;Günel JM;Carrión-Grant G;Yilmaz B;Grady C;Tanrikulu B;Bakircioğlu M;Kaymakçalan H;Caglayan AO;Sencar L;Ceyhun E;Atik AF;Bayri Y;Bai H;Kolb LE;Hebert RM;Omay SB;Mishra-Gorur K;Choi M;Overton JD;Holland EC;Mane S;State MW;Bilgüvar K;Baehring JM;Gutin PH;Piepmeier JM;Vortmeyer A;Brennan CW;Pamir MN;Kiliç T;Lifton RP;Noonan JP;Yasuno K;Günel M
通讯作者：
Günel M
影响因子：
2
作者：
Pastorino, L.;Ghiorzo, P.;Scarra, G. Bianchi
通讯作者：
Scarra, G. Bianchi