期刊
CANCERS
卷 12, 期 12, 页码 -出版社
MDPI
DOI: 10.3390/cancers12123855
关键词
metastatic melanoma; BRAF inhibitors resistance; BRAF; metabolic reprogramming; NAD; NAMPT; MAPK; oncogene; mesenchymal phenotype; stemness
类别
资金
- Gilead Fellowship program
- Ministry of Education University and Research-MIUR, PRIN Project [2017CBNCYT]
- Progetto strategico di Eccellenza Dipartimentale [D15D18000410001]
- Associazione Italiana Ricerca sul Cancro AIRC [23095]
- ITN INTEGRATA program [813284]
Simple Summary Malignant melanoma (MM) is the most fatal skin cancer due to its high metastatic potential. Treatment strategies are dramatically changing due to the introduction of BRAF/MEK inhibitors (i) and immunotherapy; however, multiple resistant mechanisms rapidly occur including metabolic rewiring. This study aimed to establish the driver role of the nicotinamide adenine dinucleotide (NAD)-biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) in BRAFi resistance development. We defined that NAMPT over-expressing MM cells were strikingly similar to cells that acquired resistance to BRAFi in terms of growth, invasion, and phenotype plasticity. These findings confirmed NAMPT as a key factor in melanoma progression and in the onset of BRAFi resistance in melanoma patients, opening new therapeutic possibilities for this subset of patients. Serine-threonine protein kinase B-RAF (BRAF)-mutated metastatic melanoma (MM) is a highly aggressive type of skin cancer. Treatment of MM patients using BRAF/MEK inhibitors (BRAFi/MEKi) eventually leads to drug resistance, limiting any clinical benefit. Herein, we demonstrated that the nicotinamide adenine dinucleotide (NAD)-biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) is a driving factor in BRAFi resistance development. Using stable and inducible NAMPT over-expression systems, we showed that forced NAMPT expression in MM BRAF-mutated cell lines led to increased energy production, MAPK activation, colony-formation capacity, and enhance tumorigenicity in vivo. Moreover, NAMPT over-expressing cells switched toward an invasive/mesenchymal phenotype, up-regulating expression of ZEB1 and TWIST, two transcription factors driving the epithelial to mesenchymal transition (EMT) process. Consistently, within the NAMPT-overexpressing cell line variants, we observed an increased percentage of a rare, drug-effluxing stem cell-like side population (SP) of cells, paralleled by up-regulation of ABCC1/MRP1 expression and CD133-positive cells. The direct correlation between NAMPT expression and gene set enrichments involving metastasis, invasiveness and mesenchymal/stemness properties were verified also in melanoma patients by analyzing The Cancer Genome Atlas (TCGA) datasets. On the other hand, CRISPR/Cas9 full knock-out NAMPT BRAFi-resistant MM cells are not viable, while inducible partial silencing drastically reduces tumor growth and aggressiveness. Overall, this work revealed that NAMPT over-expression is both necessary and sufficient to recapitulate the BRAFi-resistant phenotype plasticity.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据