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Status |
Public on May 31, 2019 |
Title |
c-Myc drives nab-paclitaxel resistance in pancreatic cancer |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by array
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Summary |
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and very often, ineffective medical and surgical therapeutic options. The treatment of patients with advanced unresectable PDAC is restricted to systemic chemotherapy, a therapeutic intervention to which most eventually develop resistance. Recently, nab-paclitaxel has been added to the arsenal of first line therapies, and the combination of gemcitabine and nab-paclitaxel has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying nab-paclitaxel (n-PTX) resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naive PDAC patients. To study the mechanisms of primary drug resistance, nab-paclitaxel-resistant (n-PTX-R) cells were generated from primary cultures and drug resistance was verified in vivo, both in zebrafish and in athymic nude mouse xenograft models. Molecular analyses identified the sustained induction of c-MYC in the nab-paclitaxel-resistant cells. Depletion of c-Myc restored nab-paclitaxel sensitivity, as did treatment with either the MEK inhibitor, trametinib, or a small molecule activator of protein phosphatase 2a (SMAP). Implications: The strategies we have devised, including the patient-derived primary cells and the unique drug resistant isogenic cells, are rapid and easily applied in vitro and in vivo platforms to better understand the mechanisms of drug resistance and for defining effective therapeutic options on a patient by patient basis
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Overall design |
Four samples included from two patients, one from each parental sample, one from the conditionally reprogrammed cell line derived from each sample. Original samples were from patients with disparate treatment regimens. This experiment was designed to determine major gene expression changes both between patients with different treatment regimens as well as confirm that pathway activation was consistent between original samples and derived cell lines.
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Contributor(s) |
Parasido E, Avetian G, Naeem A, Graham GT, Pishvaian MJ, Glasgow E, Mudambi S, Lee Y, Ihemelandu C, Choudhry MU, Peran I, Banerjee PP, Avantaggiati M, Bryant K, Baldelli E, Pierobon M, Liotta L, Petricoin EF, Fricke S, Sebastian A, Cozzitorto JA, Loots GG, Kumar D, Byers SW, London E, DiFeo A, Narla G, Winter JM, Brody JR, Rodriguez O, Albanese C |
Citation(s) |
31164413 |
Submission date |
May 24, 2019 |
Last update date |
Aug 30, 2019 |
Contact name |
Garrett Thomas Graham |
E-mail(s) |
gtg9@georgetown.edu
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Phone |
8148822017
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Organization name |
Georgetown University Medical Center
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Department |
Oncology
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Street address |
3970 Reservoir Rd NW
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City |
Washington |
State/province |
DC |
ZIP/Postal code |
20007 |
Country |
USA |
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Platforms (1) |
GPL13497 |
Agilent-026652 Whole Human Genome Microarray 4x44K v2 (Probe Name version) |
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Samples (4)
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Relations |
BioProject |
PRJNA544707 |
Supplementary file |
Size |
Download |
File type/resource |
GSE131762_RAW.tar |
8.6 Mb |
(http)(custom) |
TAR (of TXT) |
Processed data included within Sample table |
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