Defining DNA damage repair deficiency and replication stress in pancreatic cancer.

Abstract

285 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. DDR defective tumors preferentially respond to DNA damaging agents, and clinical responses to cell cycle inhibitors are seen in undefined subgroups, representing novel therapeutic strategies for PC. The aim of this study is to define and refine therapeutic segments for agents targeting DDR and replication stress in PC. Methods: We performed 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). This identified increased replication stress in a sub-group of tumours, correlating with previously defined molecular subtypes of PC, irrespective of DDR status. 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: DDR defective models, as defined by signatures of homologous recombination deficiency (HRD) were highly sensitive to Cisplatin and PARP inhibitors. Replication stress predicted differential responses to cell cycle inhibitors of WEE1, CHK1, CDK4/6 and PLK4. A novel mRNA signature of ATR inhibitor sensitivity was generated and correlated with response. Response to cell cycle checkpoint inhibitors were independent of DDR status, but strongly associated with replication stress. Conclusions: 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 predicting response to agents targeting either DDR or cell cycle checkpoints. This has led to the design and development of several personalized medicine trials via the Precision Panc platform targeting DDR and Replication stress, and will allow clinical testing of signatures of HRD and replication stress.

Immunogenicity of small‐cell lung cancer associates with STING pathway activation and is enhanced by ATR and TOP1 inhibition

“…We next set to investigate the relationship between the activation of STING pathway and cellular processes involved in DDR, DNA replication, and cell cycle progression. The observation included that STING‐low SCLC tumors exhibited activation of DDR, DNA replication, and cell cycle progression‐related pathways (Figure 4B), and their activation has been linked to high replication stress in previous studies 20,41 . Inactivation of DDR pathways was a feature of STING‐high SCLCs, which coincides with previous studies showing impaired DDR program was associated with activated cGAS‐STING pathway 42 …”

“…The observation included that STING-low SCLC tumors exhibited activation of DDR, DNA replication, and cell cycle progression-related pathways (Figure 4B), and their activation has been linked to high replication stress in previous studies. 20,41 Inactivation of DDR pathways was a feature of STING-high SCLCs, which coincides with previous studies showing impaired DDR program was associated with activated cGAS-STING pathway. 42 Further, we tested whether these three distinct STING subtypes were associated with specific genomic alterations.…”

“…An important observation is STING-low SCLC exhibited activation of pathways associated with DNA replication and cell cycle, and their activation was associated with high replication stress. 20,41 SCLCs with high replication stress were more likely to respond to DDR inhibitors. 20 DDR inhibitors, such as PARP1 and CHK1 inhibitors, can induce cytosolic DNA which initiate cGAS-STING-mediated interferon response in SCLC.…”

“…An important observation is STING‐low SCLC exhibited activation of pathways associated with DNA replication and cell cycle, and their activation was associated with high replication stress 20,41 . SCLCs with high replication stress were more likely to respond to DDR inhibitors 20 .…”

Precision Medicine in Pancreatic Cancer: Patient-Derived Organoid Pharmacotyping Is a Predictive Biomarker of Clinical Treatment Response

“…First, CA19-9 for patients presenting with low initial values, including Lewis antigen negative patients, limited the number of patients on study who were evaluable. Secondly, there are data to suggest that, unlike in metastatic disease, imaging characteristics of patients with borderline resectable and locally-advanced disease stage do not reflect the underlying response of the tumor to chemotherapy (26,27). With this in mind, RECIST criteria may not be an ideal measure of chemotherapeutic response in this work and underlies our decision to focus predominantly on the longitudinal response of CA19-9 over time.…”