Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response

Summary

The DNA-damaging agent gemcitabine (GEM) is a first-line treatment for pancreatic cancer but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs including kinase inhibitors but the experimental evidence for such rational is often unclear. Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 146 clinical targeted inhibitors and observed strong synergy for the ATR inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway including phosphorylated pS468 of CHEK1 as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations.

Dataset description

This repository contains processed data from S. Höfer et al. 2024. All curve data provided in Kinobeads.zip and decryptM.zip was processed with CurveCurator v0.4.1 (github.com/kusterlab/curve_curator). The code for data processing prior to CurveCurator can be found on Github (github.com/kusterlab/Gem_synergy), and Github_input.zip contains the required input files.