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Ref Type Journal Article
PMID (25759020)
Authors Atwood SX, Sarin KY, Whitson RJ, Li JR, Kim G, Rezaee M, Ally MS, Kim J, Yao C, Chang AL, Oro AE, Tang JY
Title Smoothened variants explain the majority of drug resistance in basal cell carcinoma.
Journal Cancer cell
Vol 27
Issue 3
Date 2015 Mar 09
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
SMO D473G missense no effect - predicted SMO D473G lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). D473G does not result in activation of Smo, as indicated by the lack of increased basal Hedgehog (Hh) pathway signaling in cell culture, and therefore, is predicted to have no effect on Smo protein function, but has been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 25759020, PMID: 25801792). Y
SMO D473H missense no effect - predicted SMO D473H lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). D473H shows similar activity to wild-type Smo in cell culture, and therefore, is predicted to have no effect on Smo protein function, but has been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 19726788, PMID: 29175550). Y
SMO D473N missense unknown SMO D473N lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). D473N has not been characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020).
SMO D473R missense gain of function - predicted SMO D473R lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). D473R is predicted to confer a gain of function to the Smo protein as demonstrated by increased Gli1 transcription in a reporter assay (PMID: 21123452) and has also been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 21123452). Y
SMO D473Y missense unknown SMO D473Y lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). D473Y is predicted to confer resistance to Hedgehog pathway inhibitors based on structural modeling (PMID: 2506392), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
SMO F460L missense gain of function - predicted SMO F460L lies within transmembrane domain 6 in the Smo protein (UniProt.org). F460L is predicted to confer a gain of function to the Smo protein as demonstrated by ligand-independent activation of Hedgehog signaling in cell culture and has also been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 25759020). Y
SMO H231R missense no effect - predicted SMO H231R lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). H231R is predicted to have no effect on Smo protein function as demonstrated by the lack of increased basal Hedgehog (Hh) pathway signaling in cell culture, but has been demonstrated to confer resistance to Hh pathway inhibitors (PMID: 25759020). Y
SMO L412F missense gain of function - predicted SMO L412F lies within transmembrane domain 5 in the Smo protein (UniProt.org). L412F is predicted to confer a gain of function to the Smo protein, as indicated by constitutive activation of Hedgehog (Hh) signaling in cell culture and has been demonstrated to confer Hh pathway inhibitor resistance (PMID: 25759020). Y
SMO Q477E missense no effect - predicted SMO Q477E lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). Q477E is predicted to have no effect on Smo protein function as demonstrated by the lack of increased basal Hedgehog (Hh) pathway signaling in cell culture, but has been demonstrated to confer resistance to Hh pathway inhibitors (PMID: 25759020). Y
SMO Q635E missense unknown SMO Q635E lies within the C-terminal cytoplasmic tail of the Smo protein (PMID: 25801792). Q635E has been described as a resistance mutation (PMID: 25759020), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Apr 2020). Y
SMO V321M missense gain of function - predicted SMO V321M lies within transmembrane domain 3 of the Smo protein (UniProt.org). V321M is predicted to confer a gain of function to the Smo protein, as demonstrated by constitutive activation of Hedgehog (Hh) signaling in cell culture and has been demonstrated to confer Hh pathway inhibitor resistance (PMID: 25759020). Y
SMO W281C missense no effect - predicted SMO W281C lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). W281C is predicted to have no effect on Smo protein function, as demonstrated by lack of increased basal Hedgehog (Hh) pathway signaling in cell culture, but has been demonstrated to confer resistance to Hh pathway inhibitors (PMID: 25759020). Y
SMO W281L missense unknown SMO W281L lies within the ligand-binding pocket of the Smo protein (PMID: 25759020). W281L has been identified in the scientific literature (PMID: 25199678), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed Apr 2020).
SMO W535L missense unknown SMO W535L lies within the transmembrane domain 7 of the Smo protein (PMID: 9422511). The functional effect of W535L is conflicting, as it results in constitutive activation of Smo and is transforming in cell culture, and has been demonstrated to confer Hedgehog pathway inhibitor resistance (PMID: 9422511, PMID: 10607393, PMID: 25759020), however in another study, W535L results in similar cell proliferation and viability levels as wild-type Smo (PMID: 29533785), and therefore, its effect on Smo protein function is unknown. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
SMO V321M Advanced Solid Tumor resistant Vismodegib Preclinical Actionable In a preclinical study, a transformed cell line expressing SMO V321M demonstrated resistance to Erivedge (vismodegib) (PMID: 25759020). 25759020
SMO W535L Advanced Solid Tumor resistant Vismodegib Preclinical Actionable In a preclinical study, a transformed cell line expressing SMO W535L demonstrated resistance to Erivedge (vismodegib) (PMID: 25759020). 25759020
SMO L412F Advanced Solid Tumor resistant Vismodegib Preclinical Actionable In a preclinical study, a transformed cell line expressing SMO L412F demonstrated resistance to Erivedge (vismodegib) (PMID: 25759020). 25759020
SMO W281C basal cell carcinoma resistant Vismodegib Preclinical Actionable In a preclinical study, a transformed cell line expressing SMO W281C was resistant to Erivedge (vismodegib) as demonstrated by elevated gene expression levels of GLI1 resulting in increased signaling of the hedgehog pathway (PMID: 25759020). 25759020
SMO H231R basal cell carcinoma resistant Vismodegib Preclinical Actionable In a preclinical study, a transformed cell line expressing SMO H231R was resistant to Erivedge (vismodegib) as demonstrated by elevated gene expression levels of GLI1 resulting in increased signaling of the hedgehog pathway (PMID: 25759020). 25759020
SMO Q477E basal cell carcinoma resistant Vismodegib Preclinical Actionable In a preclinical study, a transformed cell line expressing SMO Q477E was resistant to Erivedge (vismodegib) as demonstrated by elevated gene expression levels of GLI1 resulting in increased signaling of the hedgehog pathway (PMID: 25759020). 25759020
SMO D473G basal cell carcinoma resistant Vismodegib Preclinical Actionable In a preclinical study, a transformed cell line expressing SMO D473G was resistant to Erivedge (vismodegib) as demonstrated by elevated gene expression levels of GLI1 resulting in increased signaling of the hedgehog pathway (PMID: 25759020). 25759020
SMO F460L Advanced Solid Tumor resistant Vismodegib Preclinical Actionable In a preclinical study, a transformed cell line expressing SMO F460L demonstrated resistance to Erivedge (vismodegib) as compared to wild-type (PMID: 25759020). 25759020