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Editorial |

Hedgehog Blockade for Basal Cell Carcinoma Coming at a (Secondary Neoplastic) Price

Albert Rübben, MD1; Ralf-Dieter Hilgers, PhD2; Martin Leverkus, MD1
[+] Author Affiliations
1Department of Dermatology and Allergology, Medical Faculty of the Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
2Department of Medical Statistics, Medical Faculty of the Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany
JAMA Dermatol. 2016;152(5):521-523. doi:10.1001/jamadermatol.2015.5239.
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Hedgehog inhibitors, more accurately known as smoothened inhibitors (SIs), were introduced for the treatment of basal cell carcinoma (BCC) with much success.1 The clinical data supported the intriguing rationale of interfering with a tumor driver (overactive Sonic Hedgehog signaling in BCC) that was identified 20 years ago. Beyond the well-established surgical or conservative (radiotherapy) treatment options, treatment with SIs now represents a novel avenue the dermato-oncologist can take when surgery or radiotherapy of BCC is contraindicated.2 This extension of the therapeutic armamentarium for advanced BCC, which is currently used in patients with highly advanced tumors or basal cell nevus syndrome, has also suggested using vismodegib or sonidegib treatment in a neoadjuvant setting. However, neoadjuvant therapy would be precluded by the development of secondary resistance to vismodegib, which is mediated in the vast majority of cases by secondary mutations in smoothened.3,4

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Signaling Pathways Potentially Involved in the Development of Transdifferentiation of BCC and de Novo Development of Cutaneous SCC

A, Potential clinical outcome of smoothened (SMO) inhibition for the transdifferentiation and de novo tumor progression of cutaneous squamous cell carcinoma (SCC). B, Canonical GLI activation in basal cell carcinoma (BCC) induces target gene expression responsible for the basaloid phenotype. It is implicated in ERK suppression, resulting in suppression of the SCC phenotype. Noncanonical GLI activation through PI3K and MEK provides a synergistic EGF receptor (EGFR)–mediated input. EGFR-MEK-ERK pathway signaling induces proliferation and a squamous cell phenotype through c-MYc signaling in SCC and in RAS-mutated BCC treated with vismodegib (VD). AK indicates actinic keratosis; SI, smoothened inhibitor. aPostulated ERK suppression.

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