Smoothened Variants Explain the Majority of Drug Resistance in Basal Cell Carcinoma

被引：329

作者：

Atwood, Scott X. ^{[1
,2
]}

Sarin, Kavita Y. ^{[1
,2
]}

Whitson, Ramon J. ^{[1
,2
]}

Li, Jiang R. ^{[1
,2
]}

Kim, Geurim ^{[1
,2
]}

Rezaee, Melika ^{[1
,2
]}

Ally, Mina S. ^{[1
,2
]}

Kim, Jinah ^{[1
,2
]}

Yao, Catherine ^{[1
,2
]}

Chang, Anne Lynn S. ^{[1
,2
]}

Oro, Anthony E. ^{[1
,2
]}

Tang, Jean Y. ^{[1
,2
]}

机构：

[1] Stanford Univ, Sch Med, Program Epithelial Biol, Stanford, CA 94305 USA

[2] Stanford Univ, Sch Med, Dept Dermatol, Stanford, CA 94305 USA

来源：

CANCER CELL | 2015年 / 27卷 / 03期

关键词：

HEDGEHOG PATHWAY INHIBITION; SOMATIC MUTATIONS; MEDULLOBLASTOMA; ACTIVATION; VISMODEGIB; CANCER; RECURRENT; GROWTH;

D O I：

10.1016/j.ccell.2015.02.002

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond to aPKC-i/lambda or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.

引用

页码：342 / 353

页数：12

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