A novel predictor for stratifying pancreatic cancer patients to DNA damage checkpoint inhibitors

Introduction CHK1 is a key DNA damage checkpoint kinase involved in cell cycle arrest and DNA repair. CHK1 inhibitors (CHK1i) were originally developed as chemo-potentiators in cancers with p53 mutations. Several CHK1i have... [ view full abstract ]

Introduction

CHK1 is a key DNA damage checkpoint kinase involved in cell cycle arrest and DNA repair. CHK1 inhibitors (CHK1i) were originally developed as chemo-potentiators in cancers with p53 mutations. Several CHK1i have been in clinical evaluation recently. We have shown that cancers with oncogene-induced replicative stress are particularly susceptible to CHK1 inhibition. However, advancement of CHKi as effective therapies in the clinic requires patient stratification using predictive biomarkers of response. A novel predictor of CHK1i response identified using in vitro pharmaco-trancriptomic analysis was assessed as a potential biomarker for identifying pancreatic cancers (PaCa) responsive to combination treatment with Gemcitabine (Gem) and CHK1i.

Methods

A PaCa cell line panel was assessed for response to Gem and CHK1i currently in clinical evaluation using dose response assays. Correlation analysis of Gem or CHKi IC₅₀ with expression of our biomarker, CHK1 activation, DNA damage and DNA damage response (DDR) signalling was conducted. Combination treatments at varying doses were assessed for synergy using the excess over Bliss Independence, and the effects of pre-treatment on drug synergy was assessed to determine the influence of drug scheduling.

Results

High expression of the biomarker correlated with higher relative IC₅₀ to Gem and CHK1i drug treatment. Combination treatment of Gem+CHK1i was synergistic in the cell lines resistant to Gem, suggesting effective chemo-sensitisation in PaCa with high expression of the biomarker. Pre-treatment of PaCa lines was able to influence the level of synergy of Gem+CHK1i combination, suggesting that scheduling of treatment could influence treatment responses.

Discussion We predict that our novel biomarker will be highly beneficial in identifying patients with Gem-resistant PaCa who may benefit from combination treatment with CHKi. We also propose that drug scheduling could be utilised to enhance the efficacy of Gem+CHK1i combination treatment in this patient subgroup.

This project is made possible by an Avner Pancreatic Cancer Foundation grant  www.avnersfoundation.org.au