Basal Cell Carcinoma — SCE Dermatology MCQ

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

The correct answer is C, Smoothened (SMO) in the Hedgehog pathway. Vismodegib is an oral small-molecule inhibitor that binds directly to SMO, a transmembrane protein normally kept inactive by PTCH1. In basal cell carcinoma, loss-of-function PTCH1 mutations or activating SMO mutations cause constitutive Hedgehog signalling, driving GLI-mediated transcription and tumour proliferation. By antagonising SMO, vismodegib switches off this aberrant signalling cascade, which is why NICE recommends it for adults with symptomatic locally advanced or metastatic BCC unsuitable for surgery or radiotherapy. This mechanism is specific to BCC pathogenesis and distinguishes vismodegib from immunotherapies, VEGF inhibitors, EGFR inhibitors, or BRAF inhibitors used in other skin cancers. Why the other options are wrong: E. PD-1 checkpoint: This is the target of checkpoint inhibitors such as pembrolizumab or cemiplimab, used in advanced cutaneous squamous cell carcinoma or Merkel cell carcinoma, not vismodegib. A. VEGFR: VEGFR is targeted by anti-angiogenic agents like bevacizumab or sunitinib, relevant to renal cell carcinoma and other vascular tumours, unrelated to Hedgehog pathway inhibition. D. EGFR: EGFR inhibitors such as cetuximab or erlotinib act on a distinct tyrosine kinase pathway implicated in cutaneous squamous cell carcinoma and lung cancer, not the SMO-GLI axis driving BCC. B. BRAF kinase: BRAF inhibitors like vemurafenib and dabrafenib target mutant BRAF in melanoma, a MAPK pathway abnormality entirely separate from Hedgehog signalling. Key point: Vismodegib inhibits Smoothened, switching off aberrant Hedgehog/GLI signalling caused by PTCH1 loss, the molecular driver of most basal cell carcinomas.

Reference: NICE Technology Appraisal Guidance TA489 (2017): Vismodegib for treating basal cell carcinoma, nice.org.uk/guidance/ta489