FREQUENCY AND GENOMIC ASPECTS OF INTRINSIC RESISTANCE TO VISMODEGIB IN LOCALLY ADVANCED BASAL CELL CARCINOMA

International audiencePurpose: 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 5 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 which were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in 3 out of 5 IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyper-activation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on BCC cell line further confirmed that YAP1 overexpression increases 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 hyper-activation of HIPPO-YAP and WNT pathways