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Mol Cancer Res. 2019 Sep;17(9):1815-1827. doi: 10.1158/1541-7786.MCR-19-0191. Epub 2019 Jun 4.

The Sustained Induction of c-MYC Drives Nab-Paclitaxel Resistance in Primary Pancreatic Ductal Carcinoma Cells.

Author information

1
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.
2
Department of Biochemistry, Molecular and Cell Biology, Georgetown University Medical Center, Washington, D.C.
3
Department of Pharmacology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina.
4
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia.
5
Center for Translational Imaging, Georgetown University Medical Center, Washington, D.C.
6
Biology and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California.
7
Division of Surgical Research, Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
8
Department of Pharmaceutical Sciences, Julius L. Chambers Biomedical/Biotechnology Research Institute (JLC-BBRI), North Carolina Central University, Durham, North Carolina.
9
Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
10
Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
11
Case Western Reserve School of Medicine, Case Comprehensive Cancer Center and University Hospitals Cleveland Medical Center, Cleveland, Ohio.
12
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C. albanese@georgetown.edu.

Abstract

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 (n-PTX) has been added to the arsenal of first-line therapies, and the combination of gemcitabine and n-PTX has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying n-PTX resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naïve patients with PDAC. 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 n-PTX-R cells. Depletion of c-MYC restored n-PTX sensitivity, as did treatment with either the MEK inhibitor, trametinib, or a small-molecule activator of protein phosphatase 2a. 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.

PMID:
31164413
PMCID:
PMC6726538
[Available on 2020-03-01]
DOI:
10.1158/1541-7786.MCR-19-0191

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