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Updated: Jul 6, 2025
Cell Population Analyses During Skin Carcinogenesis
Published on: August 21, 2013
Acquisition of Drug Resistance in Basal Cell Nevus Syndrome Tumors through Basal to Squamous Cell Carcinoma
Anna R Jussila1, Daniel Haensel1, Sadhana Gaddam1
1Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA.
Abstract:
Although basal cell carcinomas arise from ectopic Hedgehog pathway activation and can be treated with pathway inhibitors, sporadic basal cell carcinomas display high resistance rates, whereas tumors arising in patients with Gorlin syndrome with germline Patched (PTCH1) alterations are uniformly suppressed by inhibitor therapy. In rare cases, patients with Gorlin syndrome on long-term inhibitor therapy will develop individual resistant tumor clones that rapidly progress, but the basis of this resistance remains unstudied. In this study, we report a case of an SMO inhibitor-resistant tumor arising in a patient with Gorlin syndrome on suppressive SMO inhibitor for nearly a decade. Using a combination of multiomics and spatial transcriptomics, we define the tumor populations at the cellular and tissue level to conclude that Gorlin tumors can develop resistance to SMO inhibitors through the previously described basal to squamous cell carcinoma transition. Intriguingly, through spatial whole-exome genomic analysis, we nominate PCYT2, ETNK1, and the phosphatidylethanolamine biosynthetic pathway as genetic suppressors of basal to squamous cell carcinoma transition resistance. These observations provide a general framework for studying tumor evolution and provide important clinical insight into mechanisms of resistance to SMO inhibitors for not only Gorlin syndrome but also sporadic basal cell carcinomas.
Insights
Gorlin syndrome tumors can develop resistance to SMO inhibitors by transitioning to squamous cell carcinoma. Genetic alterations in PCYT2 and ETNK1 may suppress this resistance, offering insights for basal cell carcinoma treatment.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Basal cell carcinomas (BCCs) originate from aberrant Hedgehog pathway signaling.
- While Hedgehog pathway inhibitors are effective, resistance is common in sporadic BCCs.
- Gorlin syndrome patients with PTCH1 alterations typically respond well to inhibitors, but resistance can emerge.
Purpose of the Study:
- To investigate the mechanisms of SMO inhibitor resistance in a Gorlin syndrome patient.
- To characterize the cellular and molecular basis of treatment resistance in BCC.
- To identify potential genetic suppressors of resistance to Hedgehog pathway inhibitors.
Main Methods:
- Multiomics analysis
- Spatial transcriptomics
- Spatial whole-exome genomic analysis
- Case study of a Gorlin syndrome patient with SMO inhibitor-resistant tumor
Main Results:
- Identified a basal cell carcinoma tumor resistant to SMO inhibitor therapy in a Gorlin syndrome patient.
- Confirmed that Gorlin tumors can acquire resistance via a basal to squamous cell carcinoma transition.
- Nominated PCYT2, ETNK1, and the phosphatidylethanolamine biosynthetic pathway as potential genetic suppressors of resistance.
Conclusions:
- Tumor evolution and resistance to SMO inhibitors can occur through a basal to squamous cell carcinoma transition.
- Specific genetic alterations, including in PCYT2 and ETNK1, may play a role in suppressing this resistance.
- Findings offer insights into resistance mechanisms for both Gorlin syndrome and sporadic basal cell carcinomas.
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