Combining gene expression analysis of gastric cancer cell lines and tumor specimens to identify biomarkers for anti-HER therapies-the role of HAS2, SHB and HBEGF.
Adaptor Proteins, Signal Transducing
/ genetics
Afatinib
/ pharmacology
Biomarkers, Tumor
/ genetics
Cell Line, Tumor
Cetuximab
/ pharmacology
Drug Resistance, Neoplasm
/ genetics
Gene Expression
/ drug effects
Heparin-binding EGF-like Growth Factor
/ genetics
Humans
Hyaluronan Synthases
/ genetics
Proto-Oncogene Proteins
/ genetics
Receptor, ErbB-2
/ drug effects
Stomach Neoplasms
/ drug therapy
Trastuzumab
/ pharmacology
Biomarker
Gastric cancer
Gene expression
HAS2
HBEGF
SHB
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
09 Mar 2022
09 Mar 2022
Historique:
received:
14
08
2021
accepted:
24
02
2022
entrez:
10
3
2022
pubmed:
11
3
2022
medline:
16
3
2022
Statut:
epublish
Résumé
The standard treatment for patients with advanced HER2-positive gastric cancer is a combination of the antibody trastuzumab and platin-fluoropyrimidine chemotherapy. As some patients do not respond to trastuzumab therapy or develop resistance during treatment, the search for alternative treatment options and biomarkers to predict therapy response is the focus of research. We compared the efficacy of trastuzumab and other HER-targeting drugs such as cetuximab and afatinib. We also hypothesized that treatment-dependent regulation of a gene indicates its importance in response and that it can therefore be used as a biomarker for patient stratification. A selection of gastric cancer cell lines (Hs746T, MKN1, MKN7 and NCI-N87) was treated with EGF, cetuximab, trastuzumab or afatinib for a period of 4 or 24 h. The effects of treatment on gene expression were measured by RNA sequencing and the resulting biomarker candidates were tested in an available cohort of gastric cancer patients from the VARIANZ trial or functionally analyzed in vitro. After treatment of the cell lines with afatinib, the highest number of regulated genes was observed, followed by cetuximab and trastuzumab. Although trastuzumab showed only relatively small effects on gene expression, BMF, HAS2 and SHB could be identified as candidate biomarkers for response to trastuzumab. Subsequent studies confirmed HAS2 and SHB as potential predictive markers for response to trastuzumab therapy in clinical samples from the VARIANZ trial. AREG, EREG and HBEGF were identified as candidate biomarkers for treatment with afatinib and cetuximab. Functional analysis confirmed that HBEGF is a resistance factor for cetuximab. By confirming HAS2, SHB and HBEGF as biomarkers for anti-HER therapies, we provide evidence that the regulation of gene expression after treatment can be used for biomarker discovery. Clinical specimens of the VARIANZ study (NCT02305043) were used to test biomarker candidates.
Sections du résumé
BACKGROUND
BACKGROUND
The standard treatment for patients with advanced HER2-positive gastric cancer is a combination of the antibody trastuzumab and platin-fluoropyrimidine chemotherapy. As some patients do not respond to trastuzumab therapy or develop resistance during treatment, the search for alternative treatment options and biomarkers to predict therapy response is the focus of research. We compared the efficacy of trastuzumab and other HER-targeting drugs such as cetuximab and afatinib. We also hypothesized that treatment-dependent regulation of a gene indicates its importance in response and that it can therefore be used as a biomarker for patient stratification.
METHODS
METHODS
A selection of gastric cancer cell lines (Hs746T, MKN1, MKN7 and NCI-N87) was treated with EGF, cetuximab, trastuzumab or afatinib for a period of 4 or 24 h. The effects of treatment on gene expression were measured by RNA sequencing and the resulting biomarker candidates were tested in an available cohort of gastric cancer patients from the VARIANZ trial or functionally analyzed in vitro.
RESULTS
RESULTS
After treatment of the cell lines with afatinib, the highest number of regulated genes was observed, followed by cetuximab and trastuzumab. Although trastuzumab showed only relatively small effects on gene expression, BMF, HAS2 and SHB could be identified as candidate biomarkers for response to trastuzumab. Subsequent studies confirmed HAS2 and SHB as potential predictive markers for response to trastuzumab therapy in clinical samples from the VARIANZ trial. AREG, EREG and HBEGF were identified as candidate biomarkers for treatment with afatinib and cetuximab. Functional analysis confirmed that HBEGF is a resistance factor for cetuximab.
CONCLUSION
CONCLUSIONS
By confirming HAS2, SHB and HBEGF as biomarkers for anti-HER therapies, we provide evidence that the regulation of gene expression after treatment can be used for biomarker discovery.
TRIAL REGISTRATION
BACKGROUND
Clinical specimens of the VARIANZ study (NCT02305043) were used to test biomarker candidates.
Identifiants
pubmed: 35264144
doi: 10.1186/s12885-022-09335-4
pii: 10.1186/s12885-022-09335-4
pmc: PMC8908634
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Biomarkers, Tumor
0
HBEGF protein, human
0
Heparin-binding EGF-like Growth Factor
0
Proto-Oncogene Proteins
0
SHB protein, human
0
Afatinib
41UD74L59M
HAS2 protein, human
EC 2.4.1.212
Hyaluronan Synthases
EC 2.4.1.212
Receptor, ErbB-2
EC 2.7.10.1
Trastuzumab
P188ANX8CK
Cetuximab
PQX0D8J21J
Banques de données
ClinicalTrials.gov
['NCT02305043']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
254Informations de copyright
© 2022. The Author(s).
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