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| Status |
Public on Jul 28, 2021 |
| Title |
The evolution of MET and NRAS gene amplification as sequential acquired resistance mechanisms in a patient with EGFR mutation positive non-small cell lung cancer |
| Organism |
Homo sapiens |
| Experiment type |
Genome variation profiling by SNP array
SNP genotyping by SNP array
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| Summary |
EGFR mutant non-small cell lung cancer patients disease demonstrates remarkable responses to EGFR targeted therapy, but inevitably they succumb to acquired resistance, which can be complex and difficult to treat. Analyzing acquired resistance through broad molecular testing is crucial to understanding the resistance mechanisms and developing new treatment options. We performed diverse clinical testing on a patient with successive stages of acquired resistance, first to an EGFR inhibitor with MET gene amplification and then subsequently to combination EGFR and MET targeted therapies. A patient-derived cell line obtained at the time of disease progression was used to identify NRAS gene amplification as an additional driver of drug resistance to combination EGFR/MET therapies. Analysis of downstream signaling revealed ERK activation that could only be eliminated by trametinib treatment, while Akt activation could be modulated by various combinations of MET, EGFR and PI3K inhibitors. Combination of an EGFR inhibitor with a MEK inhibitor was identified as a possible treatment option to overcome drug resistance related to NRAS gene amplification.
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| Overall design |
We submitted the cell line for comparative genomic hybridization (CGH) to determine whether any copy number alterations could explain the combination resistance observed in the patient-derived cell line. The data revealed numerous copy number gains and losses across most chromosomes in the cell line, including evidence for chromothrypsis of chromosome 7, with the region containing the MET gene amplified, consistent with the clinical testing results
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| Contributor(s) |
Peters TL, Brzeskiewicz PM, Nijmeh H, Le AT, Doebele RC |
| Citation(s) |
34642436 |
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| Submission date |
Jul 27, 2021 |
| Last update date |
Oct 27, 2021 |
| Contact name |
Robert Doebele |
| E-mail(s) |
[email protected]
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| Phone |
3037240033
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| Organization name |
University of Colorado-AMC
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| Department |
Medical Oncology
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| Lab |
Doebele Lab
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| Street address |
12801 E. 17th Ave
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| City |
AURORA |
| State/province |
CO |
| ZIP/Postal code |
80045 |
| Country |
USA |
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| Platforms (1) |
| GPL19718 |
IIllumina Infinium human CytoSNP-850K BeadChip |
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| Samples (1) |
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| Relations |
| BioProject |
PRJNA749956 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE180894_RAW.tar |
125.1 Mb |
(http)(custom) |
TAR (of CSV, IDAT, XLSX) |
| Processed data provided as supplementary file |
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