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Mol Cancer Res ; 17(9): 1815-1827, 2019 09.
Article in English | MEDLINE | ID: mdl-31164413

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.


Subject(s)
Albumins/pharmacology , Carcinoma, Pancreatic Ductal/genetics , Drug Resistance, Neoplasm , Paclitaxel/pharmacology , Pancreatic Neoplasms/genetics , Proto-Oncogene Proteins c-myc/genetics , Up-Regulation , Aged , Aged, 80 and over , Albumins/therapeutic use , Animals , Carcinoma, Pancreatic Ductal/drug therapy , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Neoplasm Transplantation , Paclitaxel/therapeutic use , Pancreatic Neoplasms/drug therapy , Primary Cell Culture , Tumor Cells, Cultured , Zebrafish , Pancreatic Neoplasms
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