Pooled CRISPR screening in pancreatic cancer cells implicates co-repressor complexes as a cause of multiple drug resistance via regulation of epithelial-to-mesenchymal transition

Abstract

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) patients suffer poor outcomes in part due to therapeutic resistance. We conducted four genome-wide CRISPR activation (CRISPR_act) and CRISPR knock out (CRISPR_ko) screens to identify novel resistance mechanisms to four cytotoxic chemotherapies (gemcitabine, 5-fluorouracil, irinotecan, and oxaliplatin). ABCG2, a well-described efflux pump was the strongest mediator of resistance. We showed that overexpressing HDAC1 altered promoter occupancy and expression of genes involved in the epithelial-to-mesenchymal transition. Using the results of our CRISPR screens, we predicted drug sensitivity for patients and cell lines based on gene expression profiles. These predictions could be clinically useful for treatment selection.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

* Compared to the previous version, there are two main changes. First, we incorporate new ChIP-seq and RNA-sequencing data as well as functional characterization of HDAC1 over-expression in PDAC cell lines, providing further insight into the mechanisms of drug resistance and particularly how alterations in chromatin remodeling lead to dyregulation of the epithelial-to-mesenchymal transition, ultimately contributing to drug resistance. Second, we formalize using the results of the CRISPR screens to predict drug response based on gene expression data from patient tumor tissues and pancreatic cancer cell lines, highlighting the potential clinical applications for these data.

* https://github.com/rramaker/PancDS