Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma

By R. Yauch, G. Dijkgraaf, B. Alicke, T. Januario, C. Ahn, Thomas Holcomb, Kanan D. Pujara, Jeremy Stinson, C. Callahan, T. Tang and 8 more. Science, 2009

873 citations recorded by the source corpus.

A Smooth(ened) Path to Drug Resistance The Hedgehog (Hh) signaling pathway has emerged as a key contributor to the growth of medulloblastoma, an aggressive brain tumor. GDC-0449, a drug that ramps down this signaling pathway by binding to the Hh pathway component Smoothened, was recently shown to induce rapid and dramatic tumor regression in a patient with metastatic medulloblastoma, but the tumor eventually developed resistance to the drug. Yauch et al. (p. 572, published online 3 September) show that resistance arose because the tumor acquired a mutation in Smoothened that disrupts binding of the drug. Identification of this resistance mechanism may facilitate the design of next-generation drugs for this type of cancer. A mutation that prevents binding of a promising drug lead to its target protein confers resistance in a human brain tumor. The Hedgehog (Hh) signaling pathway is inappropriately activated in certain human cancers, including medulloblastoma, an aggressive brain tumor. GDC-0449, a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), has produced promising anti-tumor responses in early clinical studies of cancers driven by mutations in this pathway. To evaluate the mechanism of resistance in a medulloblastoma patient who had relapsed after an initial response to GDC-0449, we determined the mutational status of Hh signaling genes in the tumor after disease progression. We identified an amino acid substitution at a conserved aspartic acid residue of SMO that had no effect on Hh signaling but disrupted the ability of GDC-0449 to bind SMO and suppress this pathway. A mutation altering the same amino acid also arose in a GDC-0449–resistant mouse model of medulloblastoma. These findings show that acquired mutations in a serpentine receptor with features of a G protein–coupled receptor can serve as a mechanism of drug resistance in human cancer.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6fb1f651519abaab9020c1e517a37e4bcb79c29b

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Citations in the corpus

Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition (2014, background): “Furthermore, as has been shown in both humans and mice, tumors may also rapidly acquire secondary resistance to treatment (Dijkgraaf et al., 2011; Rudin et al., 2009; Yauch et al., 2009), suggesting that such inhibitors might be ineffective as a curative option when administered as monotherapy.”
Mechanisms and insights into drug resistance in cancer (2013, background): “For instance, mutations or reduced expression of the extracellular receptor smoothened (Yauch et al., 2009; Atwood et al., 2012; Kasper and Toftgard, 2013), nucleoside transporters (Galmarini et al., 2001; Damaraju et al., 2003) or one or both folate transporters (Longo-Sorbello and Bertino, 2001)…”
Molecular subgroups of medulloblastoma: the current consensus (2011, background): “The recent demonstration that small molecules targeting smoothened (SMO) are highly effective, albeit temporarily, against Shh medulloblastoma underlines the urgent need to develop effective and practical markers for Shh medulloblastoma [6, 40, 49].”