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Smoothened variants explain the majority of drug resistance in basal cell carcinoma.

ABSTRACT: 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-?/? or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.

SUBMITTER: Atwood SX

PROVIDER: S-EPMC4357167 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Smoothened variants explain the majority of drug resistance in basal cell carcinoma.

Atwood Scott X SX Sarin Kavita Y KY Whitson Ramon J RJ Li Jiang R JR Kim Geurim G Rezaee Melika M Ally Mina S MS Kim Jinah J Yao Catherine C Chang Anne Lynn S AL Oro Anthony E AE Tang Jean Y JY

Cancer cell 20150301 3

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 r ...[more]

PMID: 25759020

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SMO variants explain the majority of drug resistance in basal cell carcinoma

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