Defining DDR deficiency and replication stress in pancreatic cancer


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Stephan Dreyer1,Viola Paulus-Hock2,Eirini-Maria Lampraki1,Rosanna Upstill-Goddard1,Giusseppina Caligiuri1,Holly Brunton3,Bryan Serrels1,Richard Cunningham1,Nigel Jamieson1,Colin McKay1,Peter Bailey1,Susie Cooke1,Andrew Biankin1,David Chang1
1University of Glasgow,2Beatson Institute of Cancer Research,3University of GLasgow

Abstract

Background

Integrated multi-omic analyses revealed 24% of pancreatic cancer (PC) harbor defects in DNA damage response (DDR) and a subgroup demonstrate upregulation in replication stress pathways. The aim of this study is to define and refine therapeutic segments for agents targeting DDR and replication stress in PC.

Method

Whole genome and RNA sequencing (RNAseq) on 48 patient-derived cell lines (PDCL) generated and characterized as part of the International Cancer Genome Initiative (ICGC) was performed.  Cytotoxic viability assays were performed using agents targeting the DDR pathway and cell cycle checkpoints, including Cisplatin, and inhibitors of PARP, ATR, WEE1, CHK1, CDK4/6 and PLK4. Subcutaneous patient derived xenografts (PDX) were generated to test therapeutic regimens in vivo.

Results

Increased replication stress was present in a sub-group of tumours, strongly correlating with previously defined molecular subtypes of PC, irrespective of DDR status. DDR defective PDCLs, as defined by signatures of homologous recombination deficiency (HRD) were highly sensitive to Cisplatin and PARP inhibitors. A novel transcriptional signature of replication stress predicted differential responses to cell cycle inhibitors of ATR, WEE1, CHK1, CDK4/6 and PLK4. Response to cell cycle checkpoint inhibitors were independent of DDR status, but strongly associated with replication stress. A BRCA1 mutant PDX model responded exceptionally to Cisplatin and PARP inhibitor monotherapy.

Conclusion

This proof of concept data demonstrates DDR deficiency and increased Replication Stress to be attractive targets in PC. Therapeutic vulnerabilities extend beyond platinum chemotherapy and can be targeted with novel small molecule inhibitors, with independent biomarkers that predict response to agents targeting either DDR or cell cycle checkpoints. This has led to the design and development of several personalized medicine trials in PC via the Precision Panc platform targeting DDR and Replication stress, and will allow clinical testing of signatures of HRD and replication stress.