Development of a protein signature to enable clinical positioning of IAP inhibitors in colorectal cancer.
Alkaline Phosphatase
/ genetics
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Caspase 8
/ genetics
Cell Line, Tumor
Colorectal Neoplasms
/ drug therapy
Dipeptides
/ pharmacology
Drug Resistance, Neoplasm
/ genetics
Fluorouracil
/ pharmacology
GPI-Linked Proteins
/ genetics
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Indoles
/ pharmacology
Inhibitor of Apoptosis Proteins
/ genetics
Neoplasm Proteins
/ genetics
Oxaliplatin
/ pharmacology
Proteomics
/ standards
Receptor-Interacting Protein Serine-Threonine Kinases
/ genetics
Transcriptome
/ drug effects
Tumor Microenvironment
/ drug effects
cell death
colorectal cancer
inhibitor of apoptosis proteins
predictive biomarkers
quantitative proteomics
Journal
The FEBS journal
ISSN: 1742-4658
Titre abrégé: FEBS J
Pays: England
ID NLM: 101229646
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
revised:
18
02
2021
received:
11
12
2020
accepted:
03
03
2021
pubmed:
5
3
2021
medline:
29
9
2021
entrez:
4
3
2021
Statut:
ppublish
Résumé
Resistance to chemotherapy-induced cell death is a major barrier to effective treatment of solid tumours such as colorectal cancer, CRC. Herein, we present a study aimed at developing a proteomics-based predictor of response to standard-of-care (SoC) chemotherapy in combination with antagonists of IAPs (inhibitors of apoptosis proteins), which have been implicated as mediators of drug resistance in CRC. We quantified the absolute expression of 19 key apoptotic proteins at baseline in a panel of 12 CRC cell lines representative of the genetic diversity seen in this disease to identify which proteins promote resistance or sensitivity to a model IAP antagonist [birinapant (Bir)] alone and in combination with SoC chemotherapy (5FU plus oxaliplatin). Quantitative western blotting demonstrated heterogeneous expression of IAP interactome proteins across the CRC cell line panel, and cell death analyses revealed a widely varied response to Bir/chemotherapy combinations. Baseline protein expression of cIAP1, caspase-8 and RIPK1 expression robustly correlated with response to Bir/chemotherapy combinations. Classifying cell lines into 'responsive', 'intermediate' and 'resistant' groups and using linear discriminant analysis (LDA) enabled the identification of a 12-protein signature that separated responders to Bir/chemotherapy combinations in the CRC cell line panel with 100% accuracy. Moreover, the LDA model was able to predict response accurately when cells were cocultured with Tumour necrosis factor-alpha to mimic a pro-inflammatory tumour microenvironment. Thus, our study provides the starting point for a proteomics-based companion diagnostic that predicts response to IAP antagonist/SoC chemotherapy combinations in CRC.
Substances chimiques
Antineoplastic Agents
0
Dipeptides
0
GPI-Linked Proteins
0
Indoles
0
Inhibitor of Apoptosis Proteins
0
Neoplasm Proteins
0
Oxaliplatin
04ZR38536J
birinapant
6O4Z07B57R
RIPK1 protein, human
EC 2.7.11.1
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
ALPI protein, human
EC 3.1.3.1
Alkaline Phosphatase
EC 3.1.3.1
Caspase 8
EC 3.4.22.-
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5374-5388Subventions
Organisme : Cancer Research UK
ID : C11884/A24387
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 110371/Z/15/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S021205/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 24387
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/T002824/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0400302
Pays : United Kingdom
Informations de copyright
© 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
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