SMO is a component of the Hedgehog signaling pathway
(Figure 1). SMO and PTCH1 are transmembrane receptor
proteins that deliver signals from
Hedgehog ligands to cells. Mutations in
PTCH1 or SMO that lead to constitutive activation of SMO are known to play a role in
carcinogenesis of basal cell carcinoma, glioblastoma, medulloblastoma, and rhabdomyosarcoma
(Onishi and Katano
The Hedgehog signaling pathway is a
critical part of embryonic development (Athar et al.
2006). In skin, Hedgehog proteins are involved in maintenance of stem cells,
development of hair follicles, development of glands, and regulation of skin growth (Athar et al.
After embryonic development, the Hedgehog pathway is not active in most human tissues (Rudin 2012).
Reactivation of this pathway can lead or contribute to carcinogenesis (Onishi and Katano
SMO was identified as a therapeutic target by Hahn et al. (1996) and Johnson
et al. (1996) (Rudin 2012).
SMO inhibitors, exemplified by cyclopamine, bind strongly to the SMO receptor, which results in suppression of Hedgehog
signaling (Robarge et
al. 2009; Rudin
Figure 1. Schematic of the Hedgehog signaling pathway.
Suggested Citation: Rudin, C. 2015. SMO. My Cancer Genome https://www.padiracinnovation.org/content/disease/basal-cell-carcinoma/smo/?tab=0
(Updated December 4).
Last Updated: December 4, 2015
SMO in Basal Cell Carcinoma
SMO mutations occur in about 12% of basal
cell carcinomas (BCC; COSMIC). Most of these mutations involve C>T
or CC>TT substitutions, which is indicative of the major cause of BCC, exposure to UVB
radiation. C>T and CC>TT mutations are UVB signature mutations (Athar et al.
The role of SMO as a prognostic or predictive factor in BCC is not yet understood. A mutation (D473H) conferring resistance to
the SMO inhibitor, vismodegib, was identified in a patient with metastatic medulloblastoma (Metcalfe and de Sauvage 2011;
Yauch et al. 2009).
D473H has not been observed in BCC at this time. Further study into mechanisms of resistance
to SMO inhibitors is needed (Rudin 2012). Table 1 shows SMO mutations
that have been observed in BCC patients (COSMIC).
Therapies targeting SMO—either approved or in development—include vismodegib,
erismodegib (LDE225), saridegib (IPI-926), BMS-833923, PF-04449913, LEQ506, and TAK-441.
Most of these bind to the extracellular domain of SMO in order to inhibit the Hedgehog
pathway. As a result, tumors that become resistant to one of these drugs are expected to be
resistant to the other drugs. Therapies to inhibit other components of the Hedgehog pathway
are under development (Rudin 2012).
Frequencies in BCC.
Suggested Citation: Rudin, C. 2015. SMO in Basal Cell Carcinoma. My Cancer
(Updated June 23).
Last Updated: June 23, 2015
SMO c.1417G>C (D473H) Mutation in Basal Cell Carcinoma
|Location of Mutation
||At the boundary between the 6th transmembrance domain and an extracellular domain
|Frequency of SMO mutations in
basal cell carcinoma
|Frequency of D473H mutation among
SMO-mutated basal cell carcinomas
||Not yet observed
|Implications for Targeted Therapeutics
|Response to vismodegib
||Hypothesized to confer decreased sensitivitya
|Response to SMO inhibitors
||Unknown at this timeb
The D473H mutation results in an amino acid substitution at position 473 in
SMO, from an aspartic acid (D) to a histidine (H).
a One mutation conferring
resistance to the SMO inhibitor vismodegib has been reported in the literature: D473H (Metcalfe and de Sauvage 2011;
Yauch et al. 2009).
This mutation was observed in a patient with medulloblastoma, not basal cell carcinoma.
b Due to the similarity between mechanism of action across SMO inhibitors
currently being investigated, it is believed that the D473H mutation may also confer decreased sensitivity (Rudin 2012).
Suggested Citation: Rudin, C. 2015. SMO c.1417G>C (D473H) Mutation in Basal Cell Carcinoma. My Cancer
(Updated March 5).
Last Updated: March 5, 2015
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