| First Author | Seidlitz T | Year | 2022 |
| Journal | EMBO Mol Med | Volume | 14 |
| Issue | 10 | Pages | e15705 |
| PubMed ID | 35993110 | Mgi Jnum | J:333658 |
| Mgi Id | MGI:7355266 | Doi | 10.15252/emmm.202215705 |
| Citation | Seidlitz T, et al. (2022) Sensitivity towards HDAC inhibition is associated with RTK/MAPK pathway activation in gastric cancer. EMBO Mol Med 14(10):e15705 |
| abstractText | 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, TGFbeta, NOTCH, and NFkappaB 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. |
