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

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.

Current treatment strategies targeting histone deacetylase inhibitors in acute lymphocytic leukemia: a systematic review

“…Despite the irreplaceable role of chemotherapeutic drugs in cancer treatment, HDACi have been demonstrated to be effective against many cancer types when used alone or in combination with other drugs (Figure 2) (9)(10)(11)(12)(13)(14). Currently there are over twenty HDACi which can be divided into pan-HDACi and specific HDACi based on their target on different classes of HDACs.…”

Gastric Organoid, a Promising Modeling for Gastric Stem Cell Homeostasis and Therapeutic Application

“…CRISPR/Cas9 represents the most efficient and effective genome editing tool and can introduce DNA double-strand breaks at the targeted locus through RNA-guided endonucleases, enabling gene knockin and knockout (43). Besides CRISPR/Cas9-mediated genetic engineering for gastric cancer modeling, traditional genetically engineered mouse model-derived organoids are also widely used to comprehend the correlation between genetic alterations and cancer phenotype (44)(45)(46)(47).…”

Novel mutations in a second primary gastric cancer in a patient treated for primary colon cancer

“…Other than histology, gastric cancers are classified according to molecular data, the cancer genome atlas (TCGA) consortium developed a molecular classification according to observed genetic alterations and grouped them into 4 subtypes, EBV positive subtype associated with Epstein Barr Virus infection, MSI type that show high frequency of microsatellite instability, genomically stable (GS) type due to CDH1 gene leading to loss of proteins related to cell adhesion; and fourth with chromosomal instability (CIN) type associated with high number of somatic copy number alterations [ 5 ]. The frequently altered genetic mutations reported is RTK/ MAPK pathway alterations associated with TP53 genetic mutations, which is most commonly associated with CIN subtype [ 6 ].…”