ZFIN ID: ZDB-PUB-190606-2
The sustained induction of c-Myc drives nab-paclitaxel resistance in primary pancreatic ductal carcinoma cells
Parasido, E., Avetian, G., Naeem, A., Graham, G., Pishvaian, M., Glasgow, E., Mudambi, S., Lee, Y., Ihemelandu, C., Choudhry, M., Peran, I., Banerjee, P.P., Avantaggiati, M.L., Bryant, K., Baldelli, E., Pierobon, M., Liotta, L., Petricoin, E., Fricke, S.T., Sebastian, A., Cozzitorto, J., Loots, G.G., Kumar, D., Byers, S., Londin, E., DiFeo, A., Narla, G., Winter, J., Brody, J.R., Rodriguez, O., Albanese, C.
Date: 2019
Source: Molecular cancer research : MCR   17(9): 1815-1827 (Journal)
Registered Authors: Glasgow, Eric
Keywords: none
MeSH Terms:
  • Aged
  • Aged, 80 and over
  • Albumins/pharmacology*
  • Albumins/therapeutic use
  • Animals
  • Carcinoma, Pancreatic Ductal/drug therapy
  • Carcinoma, Pancreatic Ductal/genetics*
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice
  • Neoplasm Transplantation
  • Paclitaxel/pharmacology*
  • Paclitaxel/therapeutic use
  • Pancreatic Neoplasms/drug therapy
  • Pancreatic Neoplasms/genetics*
  • Primary Cell Culture
  • Proto-Oncogene Proteins c-myc/genetics*
  • Tumor Cells, Cultured
  • Up-Regulation*
  • Zebrafish
PubMed: 31164413 Full text @ Mol. Cancer Res.
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 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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