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Review
. 2022 Oct 13;11(20):3210.
doi: 10.3390/cells11203210.

Novel Approaches in Non-Melanoma Skin Cancers-A Focus on Hedgehog Pathway in Basal Cell Carcinoma (BCC)

Paulina Chmiel  1 , Martyna Kłosińska  1 , Alicja Forma  2 , Zuzanna Pelc  1 , Katarzyna Gęca  1 , Magdalena Skórzewska  1
Affiliations
Review

Novel Approaches in Non-Melanoma Skin Cancers-A Focus on Hedgehog Pathway in Basal Cell Carcinoma (BCC)

Paulina Chmiel et al. Cells. .

Abstract

Basal cell carcinoma (BCC) is one of the most common neoplasms in the population. A good prognosis and mainly non-aggressive development have made it underdiagnosed and excluded from the statistics. Due to the availability of efficient surgical therapy, BCC is sometimes overlooked in the search for novel therapies. Most clinicians are unaware of its complicated pathogenesis or the availability of effective targeted therapy based on Hedgehog inhibitors (HHI) used in advanced or metastatic cases. Nevertheless, the concomitance and esthetic burden of this neoplasm are severe. As with other cancers, its pathogenesis is multifactorial and complicated with a network of dependencies. Although the tumour microenvironment (TME), genetic aberrations, and risk factors seem crucial in all skin cancers, in BCC they all have become accessible as therapeutic or prevention targets. The results of this review indicate that a central role in the development of BCC is played by the Hedgehog (Hh) signalling pathway. Two signalling molecules have been identified as the main culprits, namely Patched homologue 1 (PTCH1) and, less often, Smoothened homologue (SMO). Considering effective immunotherapy for other neoplastic growths being introduced, implementing immunotherapy in advanced BCC is pivotal and beneficial. Up to now, the US Food and Drug Administration (FDA) has approved two inhibitors of SMO for the treatment of advanced BCC. Sonidegib and vismodegib are registered based on their efficacy in clinical trials. However, despite this success, limitations might occur during the therapy, as some patients show resistance to these molecules. This review aims to summarize novel options of targeted therapies in BCC and debate the mechanisms and clinical implications of tumor resistance.

Keywords: BCC; HHI; PTCH1; SMO; Smoothened homologue; basal cell carcinoma; hedgehog inhibitors; patched homologue 1.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Outlook on primary cilia and Hedgehog signalling pathway [87]. In the absence of a Hh ligand, GLI is phosphorylated by PKA, GSK3β, and CK1, leading to GLI repressor formation and arrest of the pathway. When Hh ligands are present, Smoothened is phosphorylated, SUFU inhibition is removed, and the GLI activator induces targeted genes transcription.
Figure 2
Figure 2
The most common resistance mechanisms in Hedgehog inhibitors treatment involving canonical and non-canonical ways of activating the Hh pathway.
See this image and copyright information in PMC

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