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 - Funding Information:
We thank R. Schlegel, X. Liu, S. Agarwal, and P. Sripadhan for advice and technical support and C. Der and A. Cox for in-depth KRAS advice. C. Albanese, J.R. Brody, J. Winter, and M. Pishvaian were supported by the 2015 Pancreatic Cancer Action Network-AACR Research Acceleration Network Grant, Grant Number 15-90-25-BROD. C. Albanese, O. Rodriguez, E. Parasido, S. Byers, and E. Glasgow were funded by P30 CA051008. C. Albanese, S. Byers, and E. Parasido were funded by the Department of Energy/Lawrence Livermore National Laboratory - DE-AC52-07NA27344. C. Albanese and D. Kumar were funded by U01 CA194730. C. Ihemelandu was funded by NIH KL2TR001432. J. R. Brody and E. Londin were funded by P30 CA056036. S. Mudambi was funded by T32 CA009686. A. Sebastian and G.G. Loots performed work under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344, and were supported by LLNL-LDRD SI-17-002.
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.
UR - http://www.scopus.com/inward/record.url?scp=85071782903&partnerID=8YFLogxK
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 -