Secondary Resistance to Anti-EGFR Therapy by Transcriptional Reprogramming in Patient-Derived Colorectal Cancer Models
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA594974 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10669800.fastq.gz | Fastqsanger.gz | |||
| SRR10669801.fastq.gz | Fastqsanger.gz | |||
| SRR10669802.fastq.gz | Fastqsanger.gz | |||
| SRR10669803.fastq.gz | Fastqsanger.gz | |||
| SRR10669804.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 50 |
Similar Datasets
Project description:3' RNA-seq of patient derived colon cancer xenograft models (N=10) showing initial disease control under cetuximab treatment were collected. All xenograft models were wildtype for KRAS, NRAS, BRAF and PIK3CA. All mice were treated with cetuximab (Merck Serono) by intra peritoneal (i.p.) injection twice per week and dosed at 25mg/kg to establish response characteristics. Tumors were chronically treated to establish cetuximab secondary resistant tumors .
2021-06-14 | GSE141861 | GEO
Project description:Global mRNA expression profiling of patient derived colon cancer xenograft models (N=10) showing disease control under cetuximab treatment were collected using Agilent human whole genome array (G4845A AMADID 026652, cRNA 4x44k V2) . All xenograft models were wildtype for KRAS, NRAS, BRAF and PIK3CA. All Mice were treated with cetuximab (Merck Serono) by intra peritoneal (i.p.) injection twice per week and dosed at 25mg/kg to establish response characteristics. Tumors were chronically treated to establish cetuximab secondary resistant tumors .
2021-05-21 | GSE140973 | GEO
Project description:Secondary Resistance to Anti-EGFR Therapy by Transcriptional Reprogramming in Patient-Derived Colorectal Cancer Models
| PRJNA591603 | ENA
Project description:The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in 2 CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms. We analyzed 21 KRAS, NRAS, BRAF, and PI3K wild-type CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways.
| EGAS00001005320 | EGA
Project description:BackgroundThe development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms.MethodsWe analyzed 21 KRAS, NRAS, BRAF, and PI3K wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways.ResultsIn vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies.ConclusionsOur study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC.
| S-EPMC8283888 | biostudies-literature
Project description:Metastatic colorectal carcinoma is one of the most common cancers in the world, second most commonly diagnosed cancer in Europe. Approximately 25% of patients initially diagnosed with colorectal carcinoma have metastases at the time of the first diagnosis and almost 50% of the diagnosed patients develop metastases, which explains the high mortality rate of these tumors. The carcinogenic process can be inhibited by the inactivation of EGFR receptors, making them important therapeutic targets. However, around 90-80% of patients do not respond to the EGFR targeted therapy. Resistance is mainly due to KRAS gene mutations. In this study, we built a 171 mutations panel (OncoAlvo®) that screens all mutations recommended by the ESMO, ASCO & NICE Medical Guidelines with 99% accuracy. The samples were simultaneously genotyped by other techniques to validate our panel and accuracy.
2018-10-26 | GSE121805 | GEO
Project description:Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR), such as cetuximab and panitumumab, have evolved to important therapeutic options in metastatic colorectal cancer (CRC). However, almost all patients with clinical response to anti-EGFR therapies show disease progression within a few months and little is known about mechanism and timing of resistance evolution. Here we performed whole genome sequencing of plasma DNA (plasma-Seq) from patients treated with anti-EGFR therapy. We demonstrate that development of resistance to anti-EGFR therapies is frequently associated with focal amplifications of KRAS, MET, and ERBB2. However, we also show that focal KRAS amplifications can be acquired in tumor genomes of patients under cytotoxic chemotherapy. Furthermore, we provide evidence that specific chromosomal polysomies, such as overrepresentations of 12p and 7p, harboring KRAS and EGFR, respectively, determine responsiveness to anti-EGFR therapy. In contrast, employing ultra-sensitive deep sequencing of genes associated with anti-EGFR resistance, such as KRAS, BRAF, PIK3CA, and EGFR, we did not observe the occurrence of novel, acquired mutations. Overall, whole-genome plasma DNA sequencing represents a non-invasive blood-based surrogate measure of changes in tumors. As such, plasma-Seq enables the identification of novel mutant clones and may therefore facilitate early adjustments of therapies that may delay or prevent disease progression.
| EGAS00001000582 | EGA
Project description:Activating mutations of EGFR have been characterized as important mechanisms for carcinogenesis in a subset of EGFR-dependent non-small cell lung cancers (NSCLC). EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib, have dramatic clinical effects on EGFR-addicted lung cancers and are used as first-line therapy for EGFR-mutant tumors. However, eventually all tumors acquire secondary resistance to the drugs and progress. We established a model to better understand mechanisms of acquired resistance. NCI- HCC827 cells are EGFR-mutant and highly erlotinib-sensitive. In this study we exposed HCC827 cells to increasing concentrations of erlotinib and two highly erlotinib-resistant subclones were developed (ER3 and T15-2). In these subclones no acquired alterations of EGFR or MET were found. We hereby performed a gene expression microarray studies to understand changes that might explain mechanisms of resistance. Through these studies we demonstrated in one resistant clone (ER3) overexpression of AXL, a tyrosine kinase implicated in imatinib and lapatinib resistance. Gene expression profilings were measured in NSCLC cell line HCC827 and two erlotinib-resistant HCC827-originated sublines ER3 and T15-2.
2012-05-29 | E-GEOD-38310 | biostudies-arrayexpress
Project description:Genetic Study of anti-EGFR Antibody Therapy Response in Colorectal Carcinoma
| PRJNA498496 | ENA
Project description:Oncogene-driven lung cancers such as those with activating mutations in the epidermal growth factor receptor (EGFR) often harbor additional co-occurring genetic alterations. The significance of most alterations co-occurring with mutant EGFR remains unclear. We report the impact of loss of the mRNA splicing factor RBM10 in human EGFR mutant lung cancer. RBM10 loss decreased EGFR inhibitor efficacy in patient-derived EGFR mutant tumor models. RBM10 regulated mRNA splicing of the mitochondrial apoptotic regulator Bcl-x. Genetic inactivation of RBM10 diminished EGFR inhibitor-mediated apoptosis by altering Bcl-x splicing, decreasing Bcl-xS (pro-apoptotic) and increasing Bcl-xL (anti-apoptotic) levels. Co-inhibition of Bcl-xL and mutant EGFR overcomes resistance induced by RBM10 loss. RBM10 loss was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Inactivation of the splicing factor RBM10 is a key co-occurring genetic alteration in EGFR mutant tumors that limits EGFR inhibitor efficacy and a potential biomarker of Bcl-xL inhibitor response.
2022-06-04 | GSE199240 | GEO