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 SebastianJoseph Cozzitorto, Gabriela G. Loots, Deepak Kumar, Stephen Byers, Eric Londin, Analisa DiFeo, Goutham Narla, Jordan Winter, Jonathan R. Brody, Olga Rodriguez, Chris Albanese

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1815-1827
Number of pages13
JournalMolecular Cancer Research
Volume17
Issue number9
DOIs
StatePublished - 2019
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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