期刊
CELLS
卷 10, 期 2, 页码 -出版社
MDPI
DOI: 10.3390/cells10020431
关键词
PDAC; hexosamine biosynthetic pathway; glycosylations; KRAS; KRAS inhibitors; cancer treatment
类别
资金
- MAECI (Executive Programme of Scientific and Technological Cooperation Italy-China 2019-2021) [CN19GR03]
- Research facilitation fund (Fondo per le Agevolazioni alla Ricerca-FAR) and Fondo individuale FFABBR_NAT 2017 (MIUR, Italy)
- Key Projects of International Scientific and Technological Innovation Cooperation Between Chinese and Italian Governments [2018YFE0118600]
- University of Milano-Bicocca
- MIUR (Dipartimenti di Eccellenza 2017)
- MIUR
- Executive Programme of Scientific and Technological Cooperation Italy-China 2019-2021 [CN19GR03]
PDAC patients with KRAS mutation may benefit from a novel therapy targeting both KRAS and HBP, which could lead to negative effects on cell proliferation and survival through the suppression of important signaling pathways.
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death and the search for a resolutive therapy is still a challenge. Since KRAS is commonly mutated in PDAC and is one of the main drivers of PDAC progression, its inhibition should be a key strategy for treatment, especially considering the recent development of specific KRAS inhibitors. Nevertheless, the effects of KRAS inhibition can be increased through the co-inhibition of other nodes important for cancer development. One of them could be the hexosamine biosynthetic pathway (HBP), whose enhancement is considered fundamental for PDAC. Here, we demonstrate that PDAC cells expressing oncogenic KRAS, owing to an increase in the HBP flux, become strongly reliant on HBP for both proliferation and survival. In particular, upon treatment with two different compounds, 2-deoxyglucose and FR054, inhibiting both HBP and protein N-glycosylation, these cells undergo apoptosis significantly more than PDAC cells expressing wild-type KRAS. Importantly, we also show that the combined treatment between FR054 and the pan-RAS inhibitor BI-2852 has an additive negative effect on cell proliferation and survival by means of the suppression of both Akt activity and cyclin D1 expression. Thus, co-inhibition of HBP and oncogenic RAS may represent a novel therapy for PDAC patients.
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