期刊
CELL
卷 181, 期 2, 页码 424-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2020.03.008
关键词
-
资金
- Commonwealth Foundation for Cancer Research
- American Cancer Society (ACS) [PF-16-115-01-TBG, PF-14-066-01-TBE, GC230452]
- NWO (Rubicon Fellowship) [452182318]
- German Research Foundation
- Alan and Sandra Gerry Metastasis and Ecosystem Center
- Blavatnik Family Foundation
- NSF [1752506]
- Pershing Square Sohn Cancer Research Alliance
- Experimental Therapeutics Center at MSKCC
- V Foundation
- Abramson Family Cancer Research Institute
- Herrick Foundation endowed chair
- American Lebanese Syrian-Associated Charities of St. Jude Children's Research Hospital
- Lustgarten Foundation
- NCI [CA013106, K99 CA241110, T32 CA062948, F31 CA 232665, R01 CA215719]
- NIH [U54 OD020355, R01 CA194321, K12 CA184746, CA229803]
- MSKCC-Parker Institute for Cancer Immunotherapy
- MSKCC support grant [P30 CA008748]
KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. We show that a combination of MEK and CDK4/6 inhibitors that target KRAS-directed oncogenic signaling can suppress PDAC proliferation through induction of retinoblastoma (RB) protein-mediated senescence. In preclinical mouse models of PDAC, this senescence-inducing therapy produces a senescenceassociated secretory phenotype (SASP) that includes pro-angiogenic factors that promote tumor vascularization, which in turn enhances drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation stimulates the accumulation of CD8(+) T cells into otherwise immunologically cold'' tumors, sensitizing tumors to PD-1 checkpoint blockade. Therefore, in PDAC models, therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies through SASP-dependent effects on the tumor vasculature and immune system.
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