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Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients

ABSTRACT: Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients

PROVIDER: PRJEB34338 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR3537410.fastq.gz	Fastqsanger.gz
	ERR3537410_1.fastq.gz	Fastqsanger.gz
	ERR3537410_2.fastq.gz	Fastqsanger.gz
	ERR3537420.fastq.gz	Fastqsanger.gz
	ERR3537420_1.fastq.gz	Fastqsanger.gz

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Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients

Project description:Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4–RET and LMNA–NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.

2019-09-21 | E-MTAB-8340 | biostudies-arrayexpress

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Global gene expression analysis between cetuximab-sensitive and cetuximab-resistant colorectal cancer cells

Project description:Cetuximab is an epidermal growth factor receptor (EGFR)-blocking antibody approved for treatment of metastatic colorectal cancer. We examined differences in global gene expression between the syngeneic DiFi colorectal cancer cells, and a subline of DiFi cells with acquired resistance to cetuximab (DiFi5). We used Affymetrix HG-U133A array to compare the expression pattern of genes that are up-regulated or down-regulated between the parental DiFi colorectal cancer cells and the cetuximab-resistant DiFi5 cells. We generated a cetuximab-resistant DiFi subline, termed DiFi5, by chronic exposure of parental DiFi cells to serially increased doses of cetuximab (from 0.5 nM to 5 nM) for over 1 year. The resulting DiFi5 subline exhibits significant resistance to cetuximab-induced apoptosis. After we confirmed that the phenotype was stable over a period of time of more than 6 months, the RNA from DiFi and DiFi5 cells were extracted and hybridized to an Affymetrix HG-U133A array according to the manufacturerâs instructions. Following the hybridization, the array was scanned using a laser confocal scanner, and microarray image data were analyzed using DNA-Chip Analyzer (dChip), version 1.3, by the Sequencing and Microarray Facility at MD Anderson Cancer Center.

2016-07-17 | E-GEOD-71210 | biostudies-arrayexpress

Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients.

Project description:Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4-RET and LMNA-NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.

| S-EPMC6814827 | biostudies-other

Gene expression changes associated with acquired resistance to anti-EGFR therapy (cetuximab) in colorectal cancer cells

Project description:Despite the implementation of personalized medicine, patients with metastatic CRC (mCRC) still have a dismal overall survival due to the frequent occurrence of acquired resistance mechanisms thereby leading to clinical relapse. Understanding molecular mechanisms that support acquired resistance to anti-EGFR targeted therapy in mCRC is therefore clinically relevant and key to improving patient outcomes. Here, we observe distinct metabolic changes between cetuximab-resistant CRC cell populations, with in particular an increased glycolytic activity in KRAS-mutant cetuximab-resistant LIM1215 but not in KRAS-amplified resistant DiFi cells. We show that cetuximab-resistant LIM1215 cells have the capacity to recycle glycolysis-derived lactate to sustain their growth capacity. This is associated with an upregulation of the lactate importer MCT1 at both transcript and protein levels. Pharmacological inhibition of MCT1, with AR-C155858, reduces the uptake and oxidation of lactate and impairs growth capacity in cetuximab-resistant LIM1215 cells. This study identifies MCT1-dependent lactate utilization as a clinically actionable, metabolic vulnerability to overcome KRAS-mutant-mediated acquired resistance to anti-EGFR therapy in CRC.

2024-07-02 | GSE262796 | GEO

The expression profile of Cetuximab resistance in head-and-neck squamous cell carcinoma cells.

Project description:Cetuximab (Erbitux) is an antibody drug against EGFR and commonly used in late stage HNSCC and metastatic colorectal cancer. The oncogenic mutation of certain genes are known to drive Cetuximab resistance such as K-RAS or b-RAF mutation. The aberrant activation of signaling pathways in the presence of Cetuximab treatment to overcome cellular stress contribute to acquired resistance to Cetuximab as well. To better understand the mechanisms and molecular patterns of Cetuximab resistant cells, the Cetuximab resistant cells are trained for examining the gene expression profile. The gene expression array is used for identify the molecular signature governing the Cetuximab resitance.

2017-03-02 | GSE63916 | GEO

Transcriptomics changes in liver metastatic biopsies of colorectal carcinoma between pre-treated and acquired resistance to Cetuximab [miRNA]

Project description:Two patients who were newly diagnosed and pathologically confirmed metastatic colorectal cancer were screened for eligibility between August 2011 and December 2013 in Affiliated Hospital, Academy of Military Medical Sciences. They were treated with Cetuximab in combination with FOLFOX regimen and obtained continuous partial responses in more than six months. CT scans of liver lesions were performed every two to eight weeks. The four biopsies were evaluated by two pathologists and were confirmed that the tumor purities were greater than 50%. Each biopsy was subjected to high-throughput RNA and small RNA sequencing to obtain expression profiles of genes and miRNAs.

2019-06-20 | GSE84269 | GEO

Transcriptomics changes in liver metastatic biopsies of colorectal carcinoma between pre-treated and acquired resistance to Cetuximab [mRNA]

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Proteomics uncover EPHA2 in cetuximab resistant colorectal cancer cell lines as a potential novel therapeutic target

Project description:In metastatic colorectal cancer (mCRC), primary and acquired resistance against anti-EGFR targeted monoclonal antibodies, such as cetuximab (CET), were shown to be frequently caused by activating alterations in RAS genes (KRAS or NRAS). To this day no efficient second-line treatment options have emerged to treat mCRC upon emergence of acquired KRAS alterations. In order to uncover potential targets for second-line targeted therapies, we used mass spectrometric proteomics to shed light on kinome reprogramming in an established model of acquired, KRAS associated CET resistance. This CET resistance was reflected by significant changes in the kinome, most of them individual to each cell line. Interestingly a common theme in all investigated resistant cell lines was the upregulation of the Ephrin type-A receptor 2 (EPHA2), a well-known driver of cell migration. Expectedly resistant cell lines displayed increased migration (p<0.01) that was significantly reduced by targeting the EPHA2 signalling axis using RNA interference (p<0.001), ephrin-A1 stimulation (p<0.001), dasatinib (p<0.01) or anti-EPHA2 antibody treatment (p<0.001), identifying it as an actionable target in CET resistant mCRC. These results highlight EPHA2 and its role in KRAS mutated acquired CET resistance in mCRC and identify it as a potential target for the development of future precision medicine therapies.

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Transcriptomics changes in liver metastatic biopsies of colorectal carcinoma between pre-treated and acquired resistance to Cetuximab

Project description:Transcriptomics changes in liver metastatic biopsies of colorectal carcinoma between pre-treated and acquired resistance to Cetuximab

| PRJNA328492 | ENA

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