Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma. Issue 2 (26th September 2014)

• Record Type: Journal Article
• Authors: Pricl, Sabrina; Cortelazzi, Barbara; Dal Col, Valentina; Marson, Domenico; Laurini, Erik; Fermeglia, Maurizio; Licitra, Lisa; Pilotti, Silvana; Bossi, Paolo; Perrone, Federica
• Is Part Of: Molecular oncology. Volume 9:Issue 2(2015:Feb.)
• Page Start: 389
• Page End: 397
• Publication Date: 2014-09-26
• Subjects: Basal cell carcinoma -- Hedgehog pathway -- PTCH1 -- SMO -- Vismodegib -- Primary resistance -- Secondary resistance; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1016/j.molonc.2014.09.003
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract: Basal cell carcinomas (BCCs) and a subset of medulloblastomas are characterized by loss‐of‐function mutations in the tumor suppressor gene, PTCH1. PTCH1 normally functions by repressing the activity of the Smoothened (SMO) receptor. Inactivating PTCH1 mutations result in constitutive Hedgehog pathway activity through uncontrolled SMO signaling. Targeting this pathway with vismodegib, a novel SMO inhibitor, results in impressive tumor regression in patients harboring genetic defects in this pathway. However, a secondary mutation in SMO has been reported in medulloblastoma patients following relapse on vismodegib to date. This mutation preserves pathway activity, but appears to confer resistance by interfering with drug binding. Here we report for the first time on the molecular mechanisms of resistance to vismodegib in two BCC cases. The first case, showing progression after 2 months of continuous vismodegib (primary resistance), exhibited the new SMO G497W mutation. The second case, showing a complete clinical response after 5 months of treatment and a subsequent progression after 11 months on vismodegib (secondary resistance), exhibited a PTCH1 nonsense mutation in both the pre‐ and the post‐treatment specimens, and the SMO D473Y mutation in the post‐treatment specimens only. In silico analysis demonstrated that SMOG497W undergoes a conformational rearrangement resulting in a partial obstruction of the protein drug entry site, whereas the SMO D473Y mutation induces a direct effect on the binding site geometry leading to a total disruption of a stabilizing hydrogen bond network. Thus, the G497W and D473Y SMO mutations may represent two different mechanisms leading to primary and secondary resistance to vismodegib, respectively. Highlights: Vimsodegib is a new SMO inhibitor highly effective in basal cell carcinoma (BCC). We detected two new SMO mutations leading to vismodegib resistance in BCC. SMO G497W missense mutation results in primary resistance to vismodegib. SMO D473Y missense mutation induces secondary resistance to the inhibitor. Computer simulations unveil the molecular mechanisms underlying vismodegib resistance.