期刊
CANCER CELL
卷 27, 期 3, 页码 342-353出版社
CELL PRESS
DOI: 10.1016/j.ccell.2015.02.002
关键词
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资金
- V Foundation Translational Award
- NIAMS [5ARO54780, 2AR046786]
- NIH Pathway to Independence Award [1K99CA176847]
- Damon Runyon clinical investigator award
- American Skin Association clinical scholar award
- Stanford Cancer Institute grant
- Dermatology Foundation career development award
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.
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