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Effects of EGF, cetuximab, trastuzumab and afatinib on gene expression in gastric cancer cell lines

ABSTRACT: The antibody trastuzumab in combination with platin-fluoropyrimidine chemotherapy is the standard of care for patients with HER2-positive recurrent or metastatic gastric cancer. Alternative treatment options and biomarkers for prediction of therapy response are needed since some patients do not respond to trastuzumab therapy or develop acquired resistance. We compared the molecular effects of trastuzumab and other HER-targeting drugs cetuximab and afatinib. We also tested the hypothesis that the treatment-dependent regulation of a gene indicates its importance for response, and therefore it may be used as biomarker for patient stratification. The four gastric cancer cell lines Hs746T, MKN1, MKN7 and NCI-N87 were treated with EGF, cetuximab, trastuzumab or afatinib for 4 or 24 hours. The effect on gene expression was then measured by RNA sequencing and the resulting candidate biomarkers were tested in an available cohort of gastric cancer patients or were functionally analyzed in vitro. Treatment with afatinib resulted in the highest number of regulated genes, followed by cetuximab and trastuzumab. Although trastuzumab had little effects on gene expression, we identified BMF, HAS2 and SHB as candidate biomarkers for trastuzumab response. HAS2 and SHB were confirmed as potential predictive markers for trastuzumab therapy response in clinical specimens. AREG, EREG and HBEGF were identified as candidate biomarkers for afatinib and cetuximab treatment. The functional analysis confirmed HBEGF as 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141352 | GEO | 2020/11/02

REPOSITORIES: GEO

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Project description:Abstract Background. Epidermal growth factor receptor (EGFR) is a targetable molecule in basal-like breast cancer, which comprises most “triple negative” breast cancer (TNBC), the only breast cancer subtype without established targeted therapy. Methods. In this randomized phase II trial, metastatic TNBC patients received the anti-EGFR antibody cetuximab (250mg/kg/week iv) with carboplatin (AUC2/wk iv) added on progression, or concomitant cetuximab + carboplatin. Molecular subtyping was done on archival specimens and those with accessible tumors provided fresh tissue, before and after 7-14 days of therapy, for microarray analyses to explore EGFR pathway inhibition. Results. Of 102 TNBC patients 74% were of the basal-like molecular subtype. Response rate to cetuximab was 6% (2/31), and was 16% (4/25) to cetuximab + carboplatin after progression. Upfront cetuximab + carboplatin produced responses in 17% (12/71); 31% responded or had prolonged disease stabilization. Time to progression was 2.1 months (95% CI 1.8-5.5) and overall survival 10.4 months (95% CI 7.7-13.1) for those treated with the combination regimen. Among 16 patients with evaluable serial biopsies, genomic patterns of the EGFR pathway showed activated status in 13 and inhibition by therapy in 5. Conclusions. While most TNBC were basal-like, a significant proportion were different subtypes. The aggressive nature of metastatic TNBC leads to limited survival. Despite a promising preclinical rationale and evidence of EGFR pathway activation in most, targeted treatment with cetuximab as a single agent had marginal activity and cetuximab added to carboplatin demonstrated modest activity. Serial biopsies as part of metastatic breast cancer studies are feasible, and this study confirmed that the EGFR pathway was inhibited by therapy in only a minority suggesting ligand-independent activation in most tumors. Tissue acquisition and drug selection based upon individualized pathway activation status should be an important part of future studies of TNBC. This series contains 36 microarrays that are from 18 patients with fresh frozen tissue available from the metastatic site. Pretreatment samples (Bx0) are available for two patients. Pretreatment and post single agent treatment (7-14 days after start of treatment with cetuximab; BxSingle) are available for three patients. Pretreatment and post combination treatment (7-14 days after start of treatment with cetuximab plus carboplatin; BxCombo) are available for eight patients. Two patients have a pretreatment sample, a sample after 7-14 days of treatment with single agent cetuximab, and a third sample 7-14 days on cetuximab plus carboplatin after switching to the combination arm upon progression on the single agent arm. Samples were hybridized with Stratagene common reference spiked with RNA from two breast cancer cell lines (ME16C and MCF-7) on Custom 1x44K Agilent microarrays. Arrays were scanned on an Axon 4000B scanner and analyzed with GenePix Pro software.

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Effects of EGF, cetuximab, trastuzumab and afatinib on gene expression in gastric cancer cell lines

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