INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.
Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
Clin Cancer Res. 2022 Apr 1;28(7):1422-1432. doi: 10.1158/1078-0432.CCR-21-3764.
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.
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).
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.
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.
维莫德吉（Vismodegib）获批用于治疗局部晚期基底细胞癌（laBCC），但部分病例对该药存在内在耐药性（IR）。我们旨在评估 laBCC 中维莫德吉 IR 的频率及其潜在的基因组机制。
我们评估了 148 例 laBCC 患者对维莫德吉的反应。在一组 5 例固有耐药性基底细胞癌（IR-BCC）中进行了全面的基因组和转录组分析。
我们发现，研究队列中 6.1%的 laBCC 为 IR-BCC。先前接受化疗治疗与 IR 相关。在 5 例 IR-BCC 中有 3 例观察到先前与 BCC 或髓母细胞瘤获得性耐药（AR）相关的遗传事件。然而，IR-BCC 通过高度重排的多倍体基因组而具有独特性。功能分析表明，IR-BCC 在 RNA 和蛋白质水平上均存在 HIPPO-YAP 和 WNT 通路的过度激活。BCC 细胞系的体外实验进一步证实，YAP1 过表达可增加细胞增殖率。
laBCC 中维莫德吉 IR 较为罕见。IR-BCC 常携带 HH 通路的耐药突变，但也以 HIPPO-YAP 和 WNT 通路的过度激活为特征。
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