The following is a summary of “Acquisition of Drug Resistance in Basal Cell Nevus Syndrome Tumors through Basal to Squamous Cell Carcinoma Transition,” published in the June 2024 issue of Dermatology by Jussila, et al.
Basal cell carcinomas (BCCs) typically arise due to ectopic activation of the Hedgehog pathway and can be treated with pathway inhibitors. However, while sporadic BCCs often exhibit high resistance rates to these treatments, tumors in patients with Gorlin syndrome, who have germline Patched (PTCH1) alterations, are generally suppressed by inhibitor therapy. Rarely, patients with Gorlin syndrome undergoing long-term inhibitor therapy may develop individual resistant tumor clones that progress rapidly, although the basis for this resistance has not been studied. For a study, researchers sought to investigate the mechanisms underlying resistance to SMO inhibitors in basal cell carcinomas arising in patients with Gorlin syndrome, specifically focusing on a case of an SMO inhibitor-resistant tumor in a patient who had been on suppressive SMO inhibitor therapy for nearly a decade.
The study utilized a combination of multiomics and spatial transcriptomics to analyze the tumor populations at the cellular and tissue levels. Spatial whole-exome genomic analysis was also employed to identify potential genetic suppressors of resistance to SMO inhibitors.
The analysis revealed that Gorlin syndrome tumors can develop resistance to SMO inhibitors through a basal to squamous cell carcinoma transition, a mechanism previously described. The spatial whole-exome genomic analysis identified PCYT2, ETNK1, and the phosphatidylethanolamine biosynthetic pathway as potential genetic suppressors of this transition and resistance mechanism.
The findings suggested that Gorlin syndrome tumors can evolve resistance to SMO inhibitors via a basal to squamous cell carcinoma transition. Identifying PCYT2, ETNK1, and the phosphatidylethanolamine biosynthetic pathway as genetic suppressors provides valuable clinical insights into resistance mechanisms for both Gorlin syndrome and sporadic basal cell carcinomas. The study offered a framework for understanding tumor evolution and resistance to SMO inhibitors in these contexts.
Reference: sciencedirect.com/science/article/abs/pii/S0022202X23031998
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