An unbiased high-throughput drug screen reveals a potential therapeutic vulnerability in the most lethal molecular subtype of pancreatic cancer.

Molecular Oncology
Chun-Hao PanKenneth R Shroyer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related deaths in the United States by 2020, due in part to innate resistance to widely used chemotherapeutic agents and limited knowledge about key molecular factors that drive tumor aggression. We previously reported a novel negative prognostic biomarker, keratin 17 (K17), whose overexpression in cancer results in shortened patient survival. In this study, we aimed to determine the predictive value of K17 and explore the therapeutic vulnerability in K17-expressing PDAC, using an unbiased high-throughput drug screen. Patient-derived data analysis showed that K17 expression correlates with resistance to gemcitabine (Gem). In multiple in vitro and in vivo models of PDAC, spanning human and murine PDAC cells, and orthotopic xenografts, we determined that the expression of K17 results in a more than twofold increase in resistance to Gem and 5-fluorouracil, key components of current standard-of-care chemotherapeutic regimens. Furthermore, through an unbiased drug screen, we discovered that podophyllotoxin (PPT), a microtubule inhibitor, showed significantly higher sensitivity in K17-positive compared to K17-negative PDAC cell lines and...Continue Reading

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Citations

Jun 3, 2021·Cancer Cytopathology·Lucia Roa-PeñaKenneth R Shroyer
Aug 28, 2021·Frontiers in Cell and Developmental Biology·Hua-Yang FanXin-Hua Liang

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Methods Mentioned

BETA
Protein Assay
xenograft
Assay
flow cytometry
PMA

Software Mentioned

ModFit
CellMinerCDB
Graph Pad
symyx
compusyn
GraphPad
Synthego Inference of

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