期刊
MOLECULAR CELL
卷 77, 期 3, 页码 633-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2019.11.009
关键词
-
资金
- Melanoma Research Alliance/L'Ore' al Paris-USA Women in Science Team Science Award
- Melanoma Research Foundation
- Bloomberg Distinguished Professorship
- E.V. McCollum Chair
- Tara Miller Foundation
- [P30CA010815]
- [R01CA174746]
- [R01CA207935]
- [P01 CA114046]
- [P50 CA174523]
- [K99 CA208012-01]
- [R01 CA102184]
- [P30 CA00697356]
Metastatic melanoma is an aggressive disease, despite recent improvements in therapy. Eradicating all melanoma cells even in drug-sensitive tumors is unsuccessful in patients because a subset of cells can transition to a slow-cycling state, rendering them resistant to most targeted therapy. It is still unclear what pathways define these subpopulations and promote this resistant phenotype. In the current study, we show that Wnt5A, a non-canonical Wnt ligand that drives a metastatic, therapy-resistant phenotype, stabilizes the half-life of p53 and uses p53 to initiate a slow-cycling state following stress (DNA damage, targeted therapy, and aging). Inhibiting p53 blocks the slow-cycling phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. In vivo, this can be accomplished with a single dose of p53 inhibitor at the commencement of BRAF/MEK inhibitor therapy. These data suggest that taking the paradoxical approach of inhibiting rather than activating wild-type p53 may sensitize previously resistant metastatic melanoma cells to therapy.
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