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

• Published in: Cancer cell Vol. 27; no. 3; pp. 342 - 353
• Main Authors: Atwood, Scott X., Sarin, Kavita Y., Whitson, Ramon J., Li, Jiang R., Kim, Geurim, Rezaee, Melika, Ally, Mina S., Kim, Jinah, Yao, Catherine, Chang, Anne Lynn S., Oro, Anthony E., Tang, Jean Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09-03-2015
• Subjects: Anilides - chemistry; Anilides - therapeutic use; Binding Sites; Carcinoma, Basal Cell - drug therapy; Carcinoma, Basal Cell - genetics; Carcinoma, Basal Cell - pathology; DNA Mutational Analysis; Drug Resistance, Neoplasm - genetics; Exome; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Humans; Models, Molecular; Mutation; Protein Structure, Tertiary; Pyridines - chemistry; Pyridines - therapeutic use; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - genetics; Sequence Analysis, DNA; Signal Transduction; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Smoothened Receptor
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2015.02.002

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-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.
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•Functional SMO mutations are detected in the majority of SMO inhibitor-resistant BCCs•Resistance occurs by suppressing drug responsiveness and SMO autoinhibition•SMO mutants explain both intrinsic and acquired tumor resistance•Inhibition of aPKC-ι/λ or GLI2 bypasses SMO variants to suppress Hedgehog signaling
Atwood et al. identify key SMO mutations that confer resistance to SMO inhibitors in basal cell carcinomas (BCC) and show that these mutants respond to aPKC-ι/λ or GLI2 inhibitors, providing potential approaches for treating BCCs resistant to SMO inhibitors.