Resistance to hedgehog inhibitors in basal cell carcinoma: strategies to adopt

KEYWORDS:

• Hedgehog pathway
• basal cell carcinoma
• vismodegib
• sonidegib
• PD-1
• itraconazole

To Editor: Although surgery still represents the gold-standard treatment for the majority of basal cell carcinomas (BCCs), patients presenting with advanced BCCs, locally advanced (la) or metastatic (m) ones, not amenable with surgery or radiation therapy always require different therapeutic options [1]. Most of BCCs are characterized by an aberrant activation of the Hedgehog signaling pathway, in particular, an inactivating mutation of patched homologue 1 (PTCH1) gene, or, less often an activating mutation of Smoothened homologue (SMO) gene, leading to hedgehog signaling pathway dysregulation and consequently to the activation of GLI gene transcription, thus resulting in tumor cells differentiation and proliferation. To date, vismodegib and sonidegib are the only SMO-inhibitors FDA- and EMA-approved for the treatment of adult patients with advanced BCCs following surgery or radiotherapy or for those who are not candidates for surgery or radiation therapy [2,3]. SMO-inhibitors have also represented a valid therapeutic option in some cases of basal cell nevus syndrome, or Gorlin syndrome, in those forms associated with PTCH1 mutation; although several clinical studies have shown the efficacy and safety of vismodegib and sonidegib in treating advanced BCCs, cases of resistance to treatment due to SUFU mutations, which are downstream to SMO have been reported [4]. We read with great interest the report [5] written in response to our article entitled ‘Expert opinion on sonidegib efficacy, safety and tolerability’[6], describing genetic alterations occurring downstream of the hedgehog inhibitor target, thus conferring resistance to SMO-inhibitors.

Results from clinical studies showed a proportion of patients with advanced BCCs resistant to treatment (intrinsic resistance) and patients who develop resistance to treatment after an initial response (acquired resistance); different approaches in order to manage hedgehog pathway inhibitors (HHI)resistance, as switching HHI or using combination therapy with radiotherapy, photodynamic therapy or other downstream effectors should be considered as alternative approaches [7].

Patidegib, itraconazole and arsenic trioxide are less specific HHI under investigation to treat advanced BCCs, even though, immune checkpoint inhibitors, avoiding the interactions between programmed death 1 (PD-1) and PD-1 ligand (PD-L1), thus improving the anti-cancer immune response, have already demonstrated their efficacy as alternative therapeutic options for advanced BCCs in cases of HHI resistance [6,7]. Moreover, combination therapy could be a useful strategy to adopt in case of potential acquired resistance; the use of multiple molecules targeting different mechanisms of action may reduce the chance of resistance, increasing efficacy. Nevertheless, the adverse effects related to these drugs should be always considered and strategies in order to manage them should be considered [8,9]. As reported by the authors in their response letter, the identification of specific biomarkers of resistance or response should be at the center of future researches in order to improve the therapeutic efficacy of advanced skin tumors, thus enabling clinicians to establish a tailored therapy for each patient.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This paper was not funded.