Article Dans Une Revue Clinical Cancer Research Année : 2022

Frequency and genomic aspects of intrinsic resistance to vismodegib in locally advanced basal cell carcinoma

Antonio Alberti
Samia Mourah
Fanny Bouquet
  • Fonction : Auteur
Ariel Savina
  • Fonction : Auteur
Andrej Besse
  • Fonction : Auteur
Max Mendez-Lopez
Florent Grange
  • Fonction : Auteur
Sandrine Monestier
  • Fonction : Auteur
Laurent Mortier
  • Fonction : Auteur
Caroline Dutriaux
  • Fonction : Auteur
Philippe Saiag
  • Fonction : Auteur
Florian Herms
  • Fonction : Auteur
Jerome Lambert
  • Fonction : Auteur
Frederic de Sauvage

Résumé

Purpose: Vismodegib is approved for the treatment of locally advanced basal cell carcinoma (laBCC), but some cases demonstrate intrinsic resistance (IR) to the drug. We sought to assess the frequency of IR to vismodegib in laBCC and its underlying genomic mechanisms. Experimental design: Response to vismodegib was evaluated in a cohort of 148 laBCC patients. Comprehensive genomic and transcriptomic profiling was performed in a subset of five intrinsically resistant BCC (IR-BCC). Results: We identified that IR-BCC represents 6.1% of laBCC in the studied cohort. Prior treatment with chemotherapy was associated with IR. Genetic events that were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in three out of five IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyperactivation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on the BCC cell line further confirmed that YAP1 overexpression increases the cell proliferation rate. Conclusions: IR to vismodegib is a rare event in laBCC. IR-BCCs frequently harbor resistance mutations in the Hh pathway, but also are characterized by hyperactivation of the HIPPO-YAP and WNT pathways.

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hal-04995286 , version 1 (10-10-2025)

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Andrey Yurchenko, Oltin Pop, Meriem Ighilahriz, Ismael Padioleau, Fatemeh Rajabi, et al.. Frequency and genomic aspects of intrinsic resistance to vismodegib in locally advanced basal cell carcinoma. Clinical Cancer Research, 2022, 28 (7), pp.1422-1432. ⟨10.1158/1078-0432.CCR-21-3764⟩. ⟨hal-04995286⟩
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