Signaling Pathways and Therapeutic Strategies in Advanced Basal Cell Carcinoma

Sep 24, 2026

Non-melanoma skin cancers are the most common human neoplasms, with basal cell carcinoma (BCC) predominating in fair-skinned populations. Incidence assessment is constrained by poor registry practices, yet rates appear to be increasing. Around 85% of sporadic BCCs harbor Hedgehog-pathway gene mutations that drive aberrant GLI transcriptional activation. Management of advanced BCC remains challenging for cases not suited to surgery or radiotherapy. Hedgehog inhibitors, including vismodegib and sonidegib, have improved care but face adverse events and drug resistance, motivating updated pharmacological and emerging therapeutic strategies.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Introduction

Epidemiology

cells Review Signaling Pathways and Therapeutic Strategies in Advanced Basal Cell Carcinoma Giulia Vallini 1, *, Laura Calabrese 2,3, Costanza Canino 4, Emanuele Trovato 2, Stefano Gentileschi 5, Pietro Rubegni 2 and Linda Tognetti 2 Citation: Vallini, G.; Calabrese, L.; Canino, C.; Trovato, E.; Gentileschi, S.; Rubegni, P.; Tognetti, L. Signaling Pathways and Therapeutic Strategies in Advanced Basal Cell Carcinoma. Cells 2023, 12, 2534. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/cells12212534](10.3390/cells12212534) Academic Editor: Paul J. Higgins Received: 8 September 2023 Revised: 24 October 2023 Accepted: 25 October 2023 Published: 27 October 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy 2 Department of Medical, Surgical and Neurological Sciences, Division of Dermatology, University of Siena, 53100 Siena, Italy; [laura.calabrese@unisi.it](laura.calabrese@unisi.it) (L.C.); [emanuele.trovato@unisi.it](emanuele.trovato@unisi.it) (E.T.); [pietro.rubegni@unisi.it](pietro.rubegni@unisi.it) (P.R.); [linda.tognetti@dbm.unisi.it](linda.tognetti@dbm.unisi.it) (L.T.) 3 Institute of Dermatology, Catholic University of the Sacred Heart, 00168 Rome, Italy 4 Department of Haematology, Oncology and Cell and Gene Therapy, IRCCS Bambino Gesò Children's Hospital, 00165 Rome, Italy; [costanza.canino@opbg.net](costanza.canino@opbg.net) 5 Department of Medical, Surgical and Neurological Sciences, Division of Rheumatology, University of Siena, 53100 Siena, Italy; [stefano.gentileschi@unisi.it](stefano.gentileschi@unisi.it) * Correspondence: [giulia.vallini@student.unisi.it](giulia.vallini@student.unisi.it) Abstract: Non-melanoma skin cancers (NMSCs) are the most common human neoplasms worldwide. In detail, basal cell carcinoma (BCC) is the most frequent malignancy in the fair-skinned population. The incidence of BCC remains difﬁcult to assess due to the poor registration practice; however, it has been increasing in the last few years. Approximately, 85% of sporadic BCCs carry mutations in Hedgehog pathway genes, especially in PTCH, SUFU and SMO genes, which lead to the aberrant activation of GLI transcriptional factors, typically silent in cells of adult individuals. The management of advanced BCC (aBCC), both metastatic (mBCC) and locally advanced BCC (laBCC), not candidates for surgical excision or radiotherapy, remains challenging. The discovery of mutations in the Hh signaling pathway has paved the way for the development of Hh pathway inhibiting agents, such as vismodegib and sonidegib, which have represented a breakthrough in theaBCC management. However, the use of these agents is limited by the frequent occurrence of adverse events or the development of drug resistance. In this review, we thoroughly describe the current knowledge regarding the available options for the pharmacological management of aBCCs and provide a forward-looking update on novel therapeutic strategies that could enrich the therapeutic armamentarium of BCC in the near future. Keywords: basal cell carcinoma; Hedgehog-GLI pathway; BET; immunotherapy 1. Introduction Non-melanoma skin cancers (NMSCs) are the most common human cancer worldwide. Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) represent 99% of NMSC [1] . In detail, BCC is the most frequent malignancy in the fair-skinned population. Metastatic activity is a rare event in BCC history, as the association with death; however, the progressive growth of the tumor can be invasive and destructive [2] . At ﬁrst, BCC was thought to orig

FAQs

What genetic pathway is most commonly altered in sporadic basal cell carcinoma?

About 85% of sporadic BCCs carry mutations in Hedgehog pathway genes, especially PTCH, SUFU, and SMO, leading to aberrant activation of GLI transcription factors.

Why is managing advanced basal cell carcinoma difficult?

Advanced BCC (metastatic and locally advanced) is challenging to treat, particularly for patients who are not candidates for surgical excision or radiotherapy, and it is limited by adverse events and drug resistance with current therapies.

What therapeutic advances does the review highlight for advanced BCC?

The review describes pharmacological management options based on current knowledge of Hedgehog signaling and discusses forward-looking novel strategies intended to expand the therapeutic options for BCC.

Sep 24, 2026

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