Exploring Replication Stress Signatures for Prioritizing Combination Therapies with DNA Damage Repair Drugs

Replication stress (RS), or the accumulation of double-stranded DNA breaks, presents a therapeutic opportunity in many cancers, including breast and pancreatic tumors. When RS is present, we can target replication stress response (RSR) genes and proteins with DNA Damage Repair (DDR) drugs, such as ATR/ATM, CHK1, and WEE1 inhibitors. Here, we explore existing expression-based signatures of replication stress and assess their ability to predict in vitro drug response for this class of drugs. The replication stress phenotype is closely associated with homologous repair deficiencies (HRD), such as BRCA1/2 alterations, which can be targeted with PARP inhibitor therapies, however disentangling these two phenotypes remains a challenge.

First we assess the prevalence of RSR across cancer cell lines (using CCLE data), and then we examine key drug sensitivity and resistance features between the high RSR and the low RSR groups. We then mine for these signatures in perturbed drug screening data sets to nominate drugs for using in combo therapies.

Edits 7/8/21, with git connect/ set up.

Public Datasets

Cancer Cell Line Encyclopedia (CCLE) expression data and accompanying drug screening data through GDSC (Genomics of Drug Sensitivity in Cancer).

Internal Datasets

Mills Lab drug screens

Mills Lab MDST models

Collaborators' PDX Models and ex vivo Drug screening data

Please contact for data sharing inquiries.

Signatures

McGrail, et al. 2018 Replication Stress signature

McGrail, et al. 2017 PARPness signature

Peng, et al. 2014 Homologous Repair Deficiency (HRD) signature

GSVA Gene Set Variation Analysis using the MSIGDB Cancer Hallmarks

DNA Damage Drugs of Interest

Gemcitabine

ATR/ATM inhibitors ( AZD6738 (Ceralazertib), KU-55933, KU-60019, VE-821 )

CHK1 inhibitors ( AZD7762, MK-8776, LY2603618, PF-477736, CHIR-124 )

WEE1 inhibitors ( 681640, MK-1775 )

PARP inhibitors ( Olaparib, Niraparib, Rucaparib, Talazoparib, Veliparib )

Contact

Please email Aurora Blucher for questions, comments, or inquirues about internal dataset access.