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Sensitivity towards HDAC inhibition is associated with RTK/MAPK pathway activation in gastric cancer

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Title
Sensitivity towards HDAC inhibition is associated with RTK/MAPK pathway activation in gastric cancer
Author(s)
Seidlitz, Therese; Schmaeche, Tim; Garcia, Fernando; Lee, Joon Ho; Qin, Nan; Kochall, Susan; Fohgrub, Juliane; Pauck, David; Rothe, Alexander; Bonkyoung Koo; Weitz, Juergen; Remke, Marc; Munoz, Javier; Stange, Daniel E.
Publication Date
2022-10
Journal
EMBO MOLECULAR MEDICINE, v.14, no.10
Publisher
WILEY
Abstract
Gastric cancer ranks the fifth most common and third leading cause of cancer-related deaths worldwide. Alterations in the RTK/MAPK, WNT, cell adhesion, TP53, TGF beta, NOTCH, and NF kappa B signaling pathways could be identified as main oncogenic drivers. A combination of altered pathways can be associated with molecular subtypes of gastric cancer. In order to generate model systems to study the impact of different pathway alterations in a defined genetic background, we generated three murine organoid models: a RAS-activated (Kras(G12D), Tp53(R172H)), a WNT-activated (Apc(fl/fl), Tp53(R172H)), and a diffuse (Cdh1(fl/fl), Apc(fl/fl)) model. These organoid models were morphologically and phenotypically diverse, differed in proteome expression signatures and possessed individual drug sensitivities. A differential vulnerability to RTK/MAPK pathway interference based on the different mitogenic drivers and according to the level of dependence on the pathway could be uncovered. Furthermore, an association between RTK/MAPK pathway activity and susceptibility to HDAC inhibition was observed. This finding was further validated in patient-derived organoids from gastric adenocarcinoma, thus identifying a novel treatment approach for RTK/MAPK pathway altered gastric cancer patients.
URI
https://pr.ibs.re.kr/handle/8788114/12825
DOI
10.15252/emmm.202215705
ISSN
1757-4676
Appears in Collections:
Center for Genome Engineering(유전체 교정 연구단) > 1. Journal Papers (저널논문)
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