A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy

Abstract

Basal cell carcinoma (BCC) is the most frequent cancer in humans and results from constitutive activation of the Hedgehog pathway 1 . Several Smoothened inhibitors (Smoi) are used to treat Hedgehog-mediated malignancies, including BCC and medulloblastoma 2 . Vismodegib, a Smoi, leads to BCC shrinkage in the majority of the BCC patients 3 , but the mechanism by which it mediates BCC regression is currently unknown. Here, we used two different genetically engineered mouse models 4 to investigate the mechanisms by which Smoi mediates tumor regression. We found that vismodegib mediates BCCs regression by inhibiting hair follicle-like fate and promoting the differentiation of tumour cells (TCs). However, a small population of TCs persists and is responsible for tumour relapse following treatment discontinuation, mimicking the situation found in humans 5 . In both mouse and human BCC, this persisting slow-cycling tumour population expresses Lgr5 and is characterised by active Wnt signalling. Lgr5 lineage ablation or Wnt signalling inhibition together with vismodegib leads to BCC eradication. Our study reveals that vismodegib induces tumour regression by promoting tumour differentiation, and demonstrates that the synergy between Wnt and Smoothened inhibitors constitutes a clinically relevant strategy to overcome tumour relapse in BCC.

Complete response is reversible upon vismodegib withdrawal and re‐inducible upon vismodegib rechallenge in a patient with locally advanced basal cell carcinoma

“…Importantly, re-administration of vismodegib to mice with relapsing BCCs led again to tumour regression. 3 These findings in mice correlate well with the clinical observation; in a patient with locally advanced BCC, we report complete response upon vismodegib treatment and BCC relapse after discontinuation. Upon a second cycle of vismodegib rechallenge, complete clinical response was obtained again, suggesting a sequence of reversible and re-inducible events and proposing that the readministration of the same Hedgehog inhibitor may be efficacious for BCC recurrence in a previously responding patient.…”

“…The drug-tolerant persisting lesions induced by vismodegib (preneoplastic lesions of hyperplasia and dysplasia) were not mediated by Smo mutations, neither with loss of primary cilia. 3 Two independent publications showed that HPI agent vismodegib mediated tumour cell persistence, via a shift in tumour cell identity (transcriptional program resembling that of stem cells of the interfollicular epidermis and isthmus, instead of the hair follicle bulge) and activation of the Wnt pathway, revealing the key role of this pathway in BCC persistence, 3 in addition to its complex crosstalk with the Hedgehog signalling pathway during hair follicle morphogenesis and normal hair cycling. 4 Tumour cell persistence induced with vismodegib was fully reversible upon vismodegib withdrawal in mouse models, and there was tumour regrowth.…”

“…4 Tumour cell persistence induced with vismodegib was fully reversible upon vismodegib withdrawal in mouse models, and there was tumour regrowth. 3,5 The tumour cell persistence was re-induced upon a new cycle of vismodegib treatment. Importantly, re-administration of vismodegib to mice with relapsing BCCs led again to tumour regression.…”

“…1,2 Real-time PCR (qPCR) is considered a very efficient technique, and it adds quantitative results to clinical analyses. [3][4][5] We aimed to test the accuracy of the combination of a Novy-MacNeal-Nicolle (NNN) medium culture and TaqManbased qPCR analysis for the diagnosis of TL.…”

A Practical Guide for the Follow-Up of Patients with Advanced Basal Cell Carcinoma During Treatment with Hedgehog Pathway Inhibitors

“…These tumor cells reactivated the Hh pathway and resumed growth upon vismodegib discontinuation . Moreover, readministration of vismodegib in mice with relapsing BCCs led again to tumor regression . These findings in mice correlate well with the clinical observation in a patient with locally advanced BCC that discontinued vismodegib after complete response because of alopecia (Fig.…”