An integrated multiomics analysis of rectal cancer patients identified POU2F3 as a putative druggable target and entinostat as a cytotoxic enhancer of 5-fluorouracil.
POU2F3
multiomics analysis
neoadjuvant therapy
predictive biomarker
rectal cancer
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 07 2023
15 07 2023
Historique:
revised:
18
01
2023
received:
09
08
2022
accepted:
19
01
2023
medline:
15
5
2023
pubmed:
24
2
2023
entrez:
23
2
2023
Statut:
ppublish
Résumé
Rectal cancer (RC) accounts for one-third of colorectal cancers (CRC), and 40% of these are locally advanced rectal cancers (LARC). The use of neoadjuvant chemoradiotherapy (nCRT) significantly reduces the rate of local recurrence compared to adjuvant therapy or surgery alone. However, after nCRT, up to 40%-60% of patients show a poor pathological response, while only about 20% achieve a pathological complete response. In this scenario, the identification of novel predictors of tumor response to nCRT is urgently needed to reduce LARC mortality and to spare poorly responding patients from unnecessary treatments. Therefore, by combining gene and microRNA expression datasets with proteomic data from LARC patients, we developed an integrated network centered on seven hub-genes putatively involved in the response to nCRT. In an independent validation cohort of LARC patients, we confirmed that differential expression of NFKB1, TRAF6 and STAT3 is correlated with the response to nCRT. In addition, the functional enrichment analysis also revealed that these genes are strongly related to hallmarks of cancer and inflammation, whose dysfunction may causatively affect LARC patient's response to nCRT. Furthermore, by constructing the transcription factor-module network, we hypothesized a protective role of POU2F3 gene, which could be used as a new drug target in LARC patients. Finally, we identified and tested in vitro entinostat, a histone deacetylase inhibitor, as a chemical compound that could be combined with a classical therapeutic regimen in order to design more efficient therapeutic strategies in LARC management.
Substances chimiques
Fluorouracil
U3P01618RT
entinostat
1ZNY4FKK9H
Antineoplastic Agents
0
POU2F3 protein, human
0
Octamer Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
437-449Informations de copyright
© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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