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SMO variants explain the majority of drug resistance in basal cell carcinoma [Target Sequencing]

GSE58376 Homo sapiens Other 66 samples Submitted 2015/03/16 Platform GPL15520
Summary
Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms, providing a unique opportunity to study human tumor evolution. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs compared with 5.6% (2/36) of untreated BCCs (p<0.0001), and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket (LBP) mutations that define sites of inhibitor binding and four variants that confer constitutive activity and inhibitor resistance, thus defining pivotal residues of SMO that ensure receptor autoinhibition. Finally, we show that both classes of SMO variants respond to the aPKC-ι/λ inhibitor PSI and GLI2 antagonist ATO that operate downstream of SMO
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Also filed as BioProject PRJNA252375 and SRA study SRP043088. Searching any of these in the dataset finder brings you back here.

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