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

Journal Article · Tue Jun 04 00:00:00 EDT 2019 · Molecular Cancer Research

DOI:https://doi.org/10.1158/1541-7786.mcr-19-0191· OSTI ID:1662052

Parasido, Erika ^[1]; Avetian, George S. ^[1]; Naeem, Aisha ^[1]; Graham, Garrett  ^[1]; Pishvaian, Michael ^[1]; Glasgow, Eric ^[1]; Mudambi, Shaila ^[1]; Lee, Yichien ^[1]; Ihemelandu, Chukwuemeka ^[1]; Choudhry, Muhammad ^[1]; Peran, Ivana  ^[1]; Banerjee, Partha P. ^[1]; Avantaggiati, Maria Laura ^[1]; Bryant, Kirsten  ^[2]; Baldelli, Elisa  ^[3]; Pierobon, Mariaelena ^[3]; Liotta, Lance ^[3]; Petricoin, Emanuel ^[3]; Fricke, Stanley T. ^[1]; Sebastian, Aimy ^[4] ; Cozzitorto, Joseph ^[5]; Loots, Gabriela G. ^[4]; Kumar, Deepak  ^[6]; Byers, Stephen ^[1]; Londin, Eric ^[5]; DiFeo, Analisa  ^[7]; Narla, Goutham ^[7]; Winter, Jordan ^[8]; Brody, Jonathan R. ^[5]; Rodriguez, Olga ^[1]; Albanese, Chris ^[1]

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1. Georgetown Univ., Washington, DC (United States)
2. Univ. of North Carolina, Chapel Hill, NC (United States)
3. George Mason Univ., Fairfax, VA (United States)
4. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
5. Thomas Jefferson Univ., Philadelphia, PA (United States)
6. North Carolina Central Univ., Durham, NC (United States)
7. Univ. of Michigan, Ann Arbor, MI (United States)
8. Thomas Jefferson Univ., Philadelphia, PA (United States); Case Western Reserve Univ., Cleveland, OH (United States)

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. In this study, 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.

• Research Organization: Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
• Sponsoring Organization: USDOE National Nuclear Security Administration (NNSA); USDOE Laboratory Directed Research and Development (LDRD) Program; American Association for Cancer Research (AACR); National Institutes of Health (NIH)
• Grant/Contract Number: AC52-07NA27344; LLNL-LDRD SI-17-002; 15-90-25-BROD; P30 CA051008; U01 CA194730; NIH KL2TR001432; P30 CA056036; T32 CA009686
• OSTI ID: 1662052
• Report Number(s): LLNL-JRNL-765386; 955449
• Journal Information: Molecular Cancer Research, Vol. 17, Issue 9; ISSN 1541-7786
• Publisher: American Association for Cancer Research (AACR)
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
primary pancreatic cancer cells
conditional reprogramming
nab-paclitaxel
c-Myc