Need Help?

Genomic analysis of Smoothened inhibitor resistance in basal cell carcinoma

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 pocket. Additionally, we observe evidence of clonal selection of SMO mutations and intra-tumor heterogeneity of resistance mechanisms, which implies diverse and combinatorial strategies are required to overcome resistance.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001000881 Illumina HiSeq 2000 11
EGAD00001000887 Illumina HiSeq 2000 23
EGAD00001001125 Illumina HiSeq 2000 91
EGAD00010000678 Illumina SNP array 11
EGAD00010000680 Agilent CGH array 4
Publications Citations
Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma.
Cancer Cell 27: 2015 327-341
In silico analyses of the tumor microenvironment highlight tumoral inflammation, a Th2 cytokine shift and a mesenchymal stem cell-like phenotype in advanced in basal cell carcinomas.
J Cell Commun Signal 14: 2020 245-254
The transcriptional landscape analysis of basal cell carcinomas reveals novel signalling pathways and actionable targets.
Life Sci Alliance 4: 2021 e202000651
Comparison of the Basal Cell Carcinoma (BCC) Tumour Microenvironment to Other Solid Malignancies.
Cancers (Basel) 15: 2023 305