Genetic Study of anti-EGFR Antibody Therapy Response in Colorectal Carcinoma
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ABSTRACT:
PROVIDER: PRJNA498496 | ENA |
REPOSITORIES: ENA
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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:Purpose: Accumulating analyses of pro-oncogenic molecular mechanisms triggered a rapid development of targeted cancer therapies. Although many of these treatments produce impressive initial responses, eventual resistance onset is practically unavoidable. One of the main approaches for preventing this refractory condition relies on the implementation of combination therapies. This includes dual-specificity reagents that affect both of their targets with a high level of selectivity. Unfortunately, selection of target combinations for these treatments is often confounded by limitations in our understanding of tumor biology. Here, we describe and validate a multipronged unbiased strategy for predicting optimal co-targets for bispecific therapeutics. Experimental design: Our strategy integrates ex-vivo genome-wide loss of function screening, BioID interactome profiling and gene expression analysis of patient data to identify the best fit co-targets. Final validation of selected target combinations is done in tumorsphere cultures and xenograft models. Results: Integration of our experimental approaches unambiguously pointed towards EGFR and EPHA2 tyrosine kinase receptors as molecules of choice for co-targeting in multiple tumor types. Following this lead, we generated a human bispecific anti-EGFR/EPHA2 antibody that, as predicted, very effectively suppresses tumor growth, compared to its prototype anti-EGFR therapeutic antibody, cetuximab. Conclusion: Our work not only presents a new bispecific antibody with a high potential for being developed into clinically-relevant biologics, but more importantly, successfully validates a novel unbiased strategy for selecting biologically optimal target combinations. This is of a significant translational relevance, as such multifaceted unbiased approaches are likely to augment the development of effective combination therapies for cancer treatment.
2023-02-23 | GSE171920 | GEO
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
Project description:Colorectal cancer (CRC) is the third most common cancer world-wide with 1.2 million patients diagnosed yearly. In late stage CRC, the most commonly used targeted therapies are monoclonal antibodies cetuximab and panitumumab, which inactivate EGFR. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in CRC and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in CRC on response to anti-EGFR antibody therapy, we performed complete exome sequence and copy number analyses of 129 patient-derived tumorgrafts and targeted genomic analyses of 55 patient tumors, all of which were KRAS wild-type. We analyzed the response of tumors to anti-EGFR antibody blockade in tumorgraft models or in clinical settings. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumors with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumorgraft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluate response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and provide new avenues for intervention in the management of CRC.
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Project description:Secondary Resistance to Anti-EGFR Therapy by Transcriptional Reprogramming in Patient-Derived Colorectal Cancer Models
| PRJNA594974 | ENA
Project description:Secondary Resistance to Anti-EGFR Therapy by Transcriptional Reprogramming in Patient-Derived Colorectal Cancer Models
| PRJNA591603 | ENA
Project description:To search proteins that interact with EGFR, EGFR interactors were coimmunoprecipitated with anti-EGFR antibody from 5-8F cell extracts, separated on SDS-PAGE and stained with Coomassie blue, and non-immune IgG antibody instead of anti-EGFR antibody served as control. Interested bands were excised, and subjected to in gel trypsin digestion and liquid chromatography and high-throughput mass spectrometry (LC-MS/MS) analysis.As a result, a total of 268 proteins including ANXA1 and CBL were identified .
2024-09-18 | PXD056130 |
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.
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Project description:B cells potentially play a role in the immune response to melanoma, including during treatment with immune modulators. We profiled (transcriptome analysis) effects of anti-PD-L1 antibody therapy on gene expression in B16 melanoma tumors of B cells depleted and WT syngeneic mice. After 7 days of B16 tumors implantation, mice were treated or untreated with anti-PD-L1 antibody (every three days).
2022-05-15 | GSE202879 | GEO