mTORC1型
信号转导
抗性(生态学)
细胞生物学
生物
神经科学
PI3K/AKT/mTOR通路
生态学
作者
Akihiro Yoshida,Yiwen Bu,Shuo Qie,John Wrangle,E. Ramsay Camp,E. Starr Hazard,Gary Hardiman,Renée de Leeuw,Karen E. Knudsen,J. Alan Diehl
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2019-09-06
卷期号:5 (9)
被引量:34
标识
DOI:10.1126/sciadv.aax6352
摘要
The cyclin-dependent kinase 4/6 (CDK4/6) kinase is dysregulated in melanoma, highlighting it as a potential therapeutic target. CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern, and the molecular mechanisms of such resistance remain undefined. We demonstrate that reactivation of mammalian target of rapamycin 1 (mTORC1) signaling through increased expression of the amino acid transporter, solute carrier family 36 member 1 (SLC36A1), drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms: (i) Rb loss, which drives SLC36A1 via reduced suppression of E2f; (ii) fragile X mental retardation syndrome-associated protein 1 overexpression, which promotes SLC36A1 translation and subsequently mTORC1. Last, we demonstrate that a combination of a CDK4/6 inhibitor with an mTORC1 inhibitor has increased therapeutic efficacy in vivo, providing an important avenue for improved therapeutic intervention in aggressive melanoma.
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