Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma

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 SMO(G497W) 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.

Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines

“…Among all of the Shh-associated targeting agents, GDC-0449 (Vismodegib), a newly synthesized Smo antagonist, has shown excellent clinical efficacy in treating basal cell skin cancer and has been approved for clinical usage by the Food and Drug Administration of the USA (FDA) (21,22). To the best of our knowledge, there is little experimental and clinical evidence on whether it is effective in colon cancer, suggesting its potential use as a colon cancer therapeutic.…”

Biochemical pathways and targeted therapies in basal cell carcinoma: A systematic review

“…Although the drugs effectively inhibit SMO, there are concerns about SMO mutations and vismodegib resistance. Resistance to vismodegib after an initial successful treatment has developed predominately through SMO (D473H and G497W) mutations as well as PTCH, SHH, and GLI [8,[75][76][77] . SMO D473H is a result of aspartic acid mutating to tyrosine at position 473 whereas G497W is a mutation of glycine to tryptophan [76] .…”

“…Resistance to vismodegib after an initial successful treatment has developed predominately through SMO (D473H and G497W) mutations as well as PTCH, SHH, and GLI [8,[75][76][77] . SMO D473H is a result of aspartic acid mutating to tyrosine at position 473 whereas G497W is a mutation of glycine to tryptophan [76] . Upregulation of the IGF-1R/PI3K pathway has also been demonstrated in resistant tumor samples, as well as disruption of ligand responsiveness and autoinhibition [77,78] .…”

Association between donor and recipient smoothened gene polymorphisms and the risk of hepatocellular carcinoma recurrence following orthotopic liver transplantation in a Han Chinese population

“…The HH pathway initiates when PTCH suppression on SMO is relieved. In previous studies, SMO gene overexpressions had been reported in various cancers, including hepatocellar carcinoma [13], breast cancer [17], and basal cell carcinoma (BCL) [29]. Moreover, Pricl et al [29] had demonstrated that SMO receptor mutations played a key role in BCL and resistance to vismodegib, a kind of chemotherapy.…”