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Sensitivity towards HDAC inhibition is associated with RTK/MAPK pathway activation in gastric cancer
oleh: Therese Seidlitz, Tim Schmäche, Fernando Garcίa, Joon Ho Lee, Nan Qin, Susan Kochall, Juliane Fohgrub, David Pauck, Alexander Rothe, Bon‐Kyoung Koo, Jürgen Weitz, Marc Remke, Javier Muñoz, Daniel E Stange
Format: | Article |
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Diterbitkan: | Springer Nature 2022-10-01 |
Deskripsi
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, TGFβ, NOTCH, and NFκB 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 (KrasG12D, Tp53R172H), a WNT‐activated (Apcfl/fl, Tp53R172H), and a diffuse (Cdh1fl/fl, Apcfl/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.