Genomic analysis of Smoothened inhibitor resistance in basal cell carcinoma
|Study ID||Alternative Stable ID||Type|
Smoothened inhibitors are currently being investigated for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). The majority of BCC patients treated with vismodegib experience significant clinical benefit, however, a small number of patients develop resistance. Knowledge of resistance mechanisms can generate predictive biomarkers and is critical for the design of additional therapeutic strategies aimed at circumventing resistance. To investigate mechanisms of resistance to vismodegib in BCC we sequenced and profiled biopsies from patients who initially responded to treatment and subsequently progressed on drug.We find that resistance is associated with re-activation of the Hedgehog (Hh) pathway through diverse mechanisms, including concurrent copy number alterations in the downstream Hh pathway components SUFU and GLI2, as well as novel SMO mutations that reduce sensitivity to vismodegib. The latter fall into two classes: those that activate SMO and those that directly affect the vismodegib-binding ... (Show More)
Study Datasets 5 datasets.
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RNA sequencing of Resistant BCC samples.
|Illumina HiSeq 2000||11|
Exome sequencing of Resistant BCC samples.
|Illumina HiSeq 2000||23|
Exome sequencing of Untreated BCC samples.
|Illumina HiSeq 2000||91|
Tumor sample SNP arrays
|Illumina SNP array||11|
Tumor sample CGH arrays
|Agilent CGH array||4|
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