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Molecular Cancer Research
Molecular Cancer Research

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Cancer Genes and Networks

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

Erika Parasido, George S. Avetian, Aisha Naeem, Garrett Graham, Michael Pishvaian, Eric Glasgow, Shaila Mudambi, Yichien Lee, Chukwuemeka Ihemelandu, Muhammad Choudhry, Ivana Peran, Partha P. Banerjee, Maria Laura Avantaggiati, Kirsten Bryant, Elisa Baldelli, Mariaelena Pierobon, Lance Liotta, Emanuel Petricoin, Stanley T. Fricke, Aimy Sebastian, Joseph Cozzitorto, Gabriela G. Loots, Deepak Kumar, Stephen Byers, Eric Londin, Analisa DiFeo, Goutham Narla, Jordan Winter, Jonathan R. Brody, Olga Rodriguez and Chris Albanese
Erika Parasido
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.
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George S. Avetian
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.
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Aisha Naeem
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.
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Garrett Graham
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.
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  • ORCID record for Garrett Graham
Michael Pishvaian
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.
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Eric Glasgow
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.
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Shaila Mudambi
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.
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Yichien Lee
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.
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Chukwuemeka Ihemelandu
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.
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Muhammad Choudhry
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.
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Ivana Peran
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.
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  • ORCID record for Ivana Peran
Partha P. Banerjee
Department of Biochemistry, Molecular and Cell Biology, Georgetown University Medical Center, Washington, D.C.
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Maria Laura Avantaggiati
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.
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Kirsten Bryant
Department of Pharmacology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina.
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Elisa Baldelli
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia.
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Mariaelena Pierobon
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia.
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Lance Liotta
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia.
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Emanuel Petricoin
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia.
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Stanley T. Fricke
Center for Translational Imaging, Georgetown University Medical Center, Washington, D.C.
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Aimy Sebastian
Biology and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California.
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Joseph Cozzitorto
Division of Surgical Research, Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
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Gabriela G. Loots
Biology and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California.
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Deepak Kumar
Department of Pharmaceutical Sciences, Julius L. Chambers Biomedical/Biotechnology Research Institute (JLC-BBRI), North Carolina Central University, Durham, North Carolina.
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Stephen Byers
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.
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Eric Londin
Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
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Analisa DiFeo
Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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  • ORCID record for Analisa DiFeo
Goutham Narla
Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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Jordan Winter
Division of Surgical Research, Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.Case Western Reserve School of Medicine, Case Comprehensive Cancer Center and University Hospitals Cleveland Medical Center, Cleveland, Ohio.
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Jonathan R. Brody
Division of Surgical Research, Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
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Olga Rodriguez
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.Center for Translational Imaging, Georgetown University Medical Center, Washington, D.C.
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Chris Albanese
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C.Center for Translational Imaging, Georgetown University Medical Center, Washington, D.C.
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  • For correspondence: albanese@georgetown.edu
DOI: 10.1158/1541-7786.MCR-19-0191
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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.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2019;XX:XX–XX

  • Received February 15, 2019.
  • Revision received April 18, 2019.
  • Accepted May 31, 2019.
  • Published first June 4, 2019.
  • ©2019 American Association for Cancer Research.

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Published OnlineFirst August 2, 2019
doi: 10.1158/1541-7786.MCR-19-0191

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The Sustained Induction of c-MYC Drives Nab-paclitaxel Resistance in Primary Pancreatic Ductal Carcinoma Cells
Erika Parasido, George S. Avetian, Aisha Naeem, Garrett Graham, Michael Pishvaian, Eric Glasgow, Shaila Mudambi, Yichien Lee, Chukwuemeka Ihemelandu, Muhammad Choudhry, Ivana Peran, Partha P. Banerjee, Maria Laura Avantaggiati, Kirsten Bryant, Elisa Baldelli, Mariaelena Pierobon, Lance Liotta, Emanuel Petricoin, Stanley T. Fricke, Aimy Sebastian, Joseph Cozzitorto, Gabriela G. Loots, Deepak Kumar, Stephen Byers, Eric Londin, Analisa DiFeo, Goutham Narla, Jordan Winter, Jonathan R. Brody, Olga Rodriguez and Chris Albanese
Mol Cancer Res August 2 2019 DOI: 10.1158/1541-7786.MCR-19-0191

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The Sustained Induction of c-MYC Drives Nab-paclitaxel Resistance in Primary Pancreatic Ductal Carcinoma Cells
Erika Parasido, George S. Avetian, Aisha Naeem, Garrett Graham, Michael Pishvaian, Eric Glasgow, Shaila Mudambi, Yichien Lee, Chukwuemeka Ihemelandu, Muhammad Choudhry, Ivana Peran, Partha P. Banerjee, Maria Laura Avantaggiati, Kirsten Bryant, Elisa Baldelli, Mariaelena Pierobon, Lance Liotta, Emanuel Petricoin, Stanley T. Fricke, Aimy Sebastian, Joseph Cozzitorto, Gabriela G. Loots, Deepak Kumar, Stephen Byers, Eric Londin, Analisa DiFeo, Goutham Narla, Jordan Winter, Jonathan R. Brody, Olga Rodriguez and Chris Albanese
Mol Cancer Res August 2 2019 DOI: 10.1158/1541-7786.MCR-19-0191
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