Basal Cell Carcinoma — SCE Dermatology MCQ

Correct answer: E — Smoothened (SMO) in the Hedgehog pathway

The correct answer is E, Smoothened (SMO) in the Hedgehog pathway. Both sonidegib and vismodegib are oral Hedgehog pathway inhibitors that bind to and inhibit the transmembrane protein Smoothened, which lies downstream of the Patched-1 (PTCH1) receptor and is constitutively activated in the great majority of basal cell carcinomas through PTCH1 loss-of-function or SMO gain-of-function mutations. By blocking SMO, these drugs prevent activation of GLI transcription factors and downstream oncogenic signalling, giving them antitumour activity in locally advanced or metastatic BCC unsuitable for surgery or radiotherapy. Sonidegib is recommended by NICE as an option for adults with this indication where vismodegib is unsuitable, reflecting its identical mechanistic class. Why the other options are wrong: D. PD-1: PD-1 is targeted by checkpoint inhibitors such as cemiplimab, used in advanced BCC after Hedgehog inhibitor failure, not by sonidegib or vismodegib. A. EGFR: EGFR is the target of drugs like erlotinib and cetuximab, relevant in other cancers such as lung and colorectal cancer, and is not the mechanism of Hedgehog pathway inhibitors. B. VEGFR: VEGFR is targeted by antiangiogenic agents such as bevacizumab and sunitinib, unrelated to Hedgehog signalling in BCC. C. BRAF: BRAF inhibitors such as vemurafenib and dabrafenib treat BRAF-mutant melanoma, a different oncogenic driver entirely unrelated to SMO or Hedgehog signalling. Key point: Sonidegib and vismodegib are both Smoothened inhibitors that block aberrant Hedgehog pathway signalling driven by PTCH1 or SMO mutations in basal cell carcinoma.

Reference: NICE Technology Appraisal Guidance TA774: Sonidegib for treating basal cell carcinoma (2022), nice.org.uk/guidance/ta774