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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58377 | GEO | 2015/03/16

SECONDARY ACCESSION(S): PRJNA252374

REPOSITORIES: GEO

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

Project description: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

2015-03-16 | GSE58376 | GEO

SMO variants explain the majority of drug resistance in basal cell carcinoma [RNA-Seq]

2015-03-16 | GSE58375 | GEO

SMO variants explain the majority of drug resistance in basal cell carcinoma [exome-seq]

2015-03-16 | GSE58374 | GEO

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

Project description: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.

| S-EPMC4357167 | biostudies-literature

Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma.

Project description:Basal cell carcinomas (BCCs) and a subset of medulloblastomas are characterized by loss-of-function mutations in the tumor suppressor gene, PTCH1. PTCH1 normally functions by repressing the activity of the Smoothened (SMO) receptor. Inactivating PTCH1 mutations result in constitutive Hedgehog pathway activity through uncontrolled SMO signaling. Targeting this pathway with vismodegib, a novel SMO inhibitor, results in impressive tumor regression in patients harboring genetic defects in this pathway. However, a secondary mutation in SMO has been reported in medulloblastoma patients following relapse on vismodegib to date. This mutation preserves pathway activity, but appears to confer resistance by interfering with drug binding. Here we report for the first time on the molecular mechanisms of resistance to vismodegib in two BCC cases. The first case, showing progression after 2 months of continuous vismodegib (primary resistance), exhibited the new SMO G497W mutation. The second case, showing a complete clinical response after 5 months of treatment and a subsequent progression after 11 months on vismodegib (secondary resistance), exhibited a PTCH1 nonsense mutation in both the pre- and the post-treatment specimens, and the SMO D473Y mutation in the post-treatment specimens only. In silico analysis demonstrated that SMO(G497W) undergoes a conformational rearrangement resulting in a partial obstruction of the protein drug entry site, whereas the SMO D473Y mutation induces a direct effect on the binding site geometry leading to a total disruption of a stabilizing hydrogen bond network. Thus, the G497W and D473Y SMO mutations may represent two different mechanisms leading to primary and secondary resistance to vismodegib, respectively.

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Project description:This SuperSeries is composed of the SubSeries listed below.

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Transcriptional profiling of quinidine drug resistance genes in Candida albicans

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-03-01 | E-GEOD-41535 | biostudies-arrayexpress

Anti-BRAF mutation drug resistance enhances EGFR expression in melanomas

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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A transposon screen identifies loss of primary cilia as a mechanism of resistance to Smo inhibitors

Project description:This SuperSeries is composed of the SubSeries listed below.

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Common genetic variants explain the majority of the correlation between height and intelligence: the generation Scotland study.

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