TY - JOUR
T1 - The sustained induction of c-MYC drives nab-paclitaxel resistance in primary pancreatic ductal carcinoma cells
AU - Parasido, Erika
AU - Avetian, George S.
AU - Naeem, Aisha
AU - Graham, Garrett
AU - Pishvaian, Michael
AU - Glasgow, Eric
AU - Mudambi, Shaila
AU - Lee, Yichien
AU - Ihemelandu, Chukwuemeka
AU - Choudhry, Muhammad
AU - Peran, Ivana
AU - Banerjee, Partha P.
AU - Avantaggiati, Maria Laura
AU - Bryant, Kirsten
AU - Baldelli, Elisa
AU - Pierobon, Mariaelena
AU - Liotta, Lance
AU - Petricoin, Emanuel
AU - Fricke, Stanley T.
AU - Sebastian, Aimy
AU - Cozzitorto, Joseph
AU - Loots, Gabriela G.
AU - Kumar, Deepak
AU - Byers, Stephen
AU - Londin, Eric
AU - DiFeo, Analisa
AU - Narla, Goutham
AU - Winter, Jordan
AU - Brody, Jonathan R.
AU - Rodriguez, Olga
AU - Albanese, Chris
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-19-0191
DO - 10.1158/1541-7786.MCR-19-0191
M3 - Article
C2 - 31164413
AN - SCOPUS:85071782903
SN - 1541-7786
VL - 17
SP - 1815
EP - 1827
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 9
ER -