• What is SMO?
  • SMO in Basal Cell Carcinoma
  • SMO c.1046_1047delCCinsTT (T349I)
  • Clinical Trials


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 2011).

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. 2006).

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 2011).

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 2012).


Figure 1. Schematic of the Hedgehog signaling pathway.

Related Pathways

Contributors: Charles Rudin, M.D., Ph.D.

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. 2006).

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).

Table 1. SMO Mutation Frequencies in BCC.
Gene Amino Acid Change Nucleotide Change Frequency Among SMO-Mutated BCC (COSMIC)
SMO p.A68V c.203_204delCCinsTT 6%
p.R199W c.595C>T 12%
p.T349I c.1046_1047delCCinsTT 6%
p.D473H c.1417G>C​ 0%​
p.R485W c.1452_1453delCCinsTT 6%
p.L515F c.1542_1543delCCinsTT 6%
p.W535L c.1604G>T 47%
p.R562Q c.1685G>A 6%
p.A652V c.1955C>T 6%
p.P755F c.2263_2264delCCinsTT​ 6%


Contributors: Charles Rudin, M.D., Ph.D.

Suggested Citation: Rudin, C. 2015. SMO in Basal Cell Carcinoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/basal-cell-carcinoma/smo/ (Updated June 23).

Last Updated: June 23, 2015

SMO c.1046_1047delCCinsTT (T349I) Mutation in Basal Cell Carcinoma

Location of Mutation Cytoplasmic domain (UniProt Consortium 2012)
Frequency of SMO mutations in basal cell carcinoma 12% (COSMIC)
Frequency of T349I mutation among SMO-mutated
 basal cell carcinomas
6% (COSMIC)​
Implications for Targeted Therapeutics
Response to SMO inhibitors Unknown at this timea

The T349I mutation results in an amino acid substitution at position 349 in SMO, from a threonine (T) to an isoleucine (I).

a The effects of specific mutations on efficacy of SMO inhibitors have not yet been studied, with the exception of D473H (see SMO c.1417G>C (D473H) Mutation in Medulloblastoma​ page for more information).

Contributors: Charles Rudin, M.D., Ph.D.

Suggested Citation: Rudin, C. 2015. SMO c.1046_1047delCCinsTT (T349I) Mutation in Basal Cell Carcinoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/basal-cell-carcinoma/smo/166/ (Updated June 19).

Last Updated: June 19, 2015

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