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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

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.

Details

Original languageEnglish
Article numbere15705
JournalEMBO molecular medicine
Volume14
Issue number10
Publication statusPublished - 10 Oct 2022
Peer-reviewedYes

External IDs

PubMed 35993110
ORCID /0000-0001-7367-5525/work/151437329

Keywords

Sustainable Development Goals

ASJC Scopus subject areas

Keywords

  • gastric cancer, HDACi, MAPK, organoids

Library keywords