Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma

Abstract

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.

Recent advances in the role of Yes‐associated protein in dermatosis

“…53 Hyperactivation of Hippo/YAP and WNT pathways was observed in intrinsically resistant BCC. 49 At the same time, YAP promotes the development of BCC through the c-JUN/activator protein 1 (AP1) axis independent of the WNT and Hedgehog pathways. 16 YAP and its downstream effectors CCN1 and CCN2 were found to be upregulated in the skin of patients with BCC, and elevated levels of CCN family proteins were significantly correlated with tumor malignancy.…”

“…48 In YAP-overexpressing mouse BCC cell lines, the rate of proliferation rate was found to be increased 2.1 fold relative to control cells. 49 Aberrant WNT and Hedgehog signaling is thought to underlie BCC. 50 The interaction between Hedgehog and YAP also controls epidermis development and homeostasis, 51 and a positive feedback interaction between these factors can promote the development of BCC.…”

“…Genome‐wide analysis of BCC samples has revealed an upregulation of YAP target genes 48 . In YAP‐overexpressing mouse BCC cell lines, the rate of proliferation rate was found to be increased 2.1 fold relative to control cells 49 . Aberrant WNT and Hedgehog signaling is thought to underlie BCC 50 .…”

“…Disruption of the Gαs/PKA interaction induced cell‐autonomous Hedgehog signaling and activation of YAP, leading to the development of mouse and human BCC 53 . Hyperactivation of Hippo/YAP and WNT pathways was observed in intrinsically resistant BCC 49 . At the same time, YAP promotes the development of BCC through the c‐JUN/activator protein 1 (AP1) axis independent of the WNT and Hedgehog pathways 16 .…”

Long-Term Management of Advanced Basal Cell Carcinoma: Current Challenges and Future Perspectives

“…However, some patients may be resistant to treatment, termed intrinsic resistance, or may develop resistance to treatment after the initial response, termed acquired resistance [ 50 ]. Numbers of acquired resistance on HHIs are not known from pivotal studies, but the occurrence of intrinsic and acquired resistance was investigated in a subset of 148 patients of the STEVIE study [ 51 ]. In this trial 9 patients (6.1%) discontinued treatment because of intrinsic resistance and 14 patients (9.5%) because of acquired resistance.…”