Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Abstract

Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting the DNA damage response (DDR) and replication stress. We show that patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum and PARP inhibitor therapy in vitro and in vivo. We generated a novel signature of replication stress with potential clinical utility in predicting response to ATR and WEE1 inhibitor treatment. Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy.

Defining the KRAS-regulated kinome in KRAS-mutant pancreatic cancer

“…We showed previously that pharmacologic inhibition of TTK impaired PDAC growth (64). In agreement with previous studies (59,(65)(66)(67), we showed here that inhibition of WEE1 suppresses PDAC growth. Additionally, we found that concurrent ERK inhibition, to counter the compensatory ERK activation associated with WEE1 inhibition, further enhanced WEE1i growth-inhibitory activity.…”

Poly(ADP‐ribose) polymerase inhibition in pancreatic cancer

“…Interestingly, HRD was not associated with any of the transcription subtypes. In a recent study with 62 patient‐derived PDAC cell lines, predictive biomarkers for HRD and response to platinum derivates and olaparib were described that also identify patients without mutations in the key HRR genes 38 . These results indicate that the number of patients that might benefit from PARPi therapy is possibly not limited to patients with germline BRCA1/2 mutations.…”

“…Interestingly, sequential therapy involving PARPi and cell cycle checkpoint inhibitors can work not only in HRD tumors but also in tumors without HRD 45 . Tumor cells with high‐endogenous replication stress are more susceptible to therapy with cell cycle checkpoint inhibitors 38 . In PDAC, the basal/squamous subtype has increased endogenous replication stress relative to the classical subtype, and basal/squamous tumors are therefore more likely to be susceptible to cell cycle checkpoint inhibitors irrespective of HR deficiency status.…”

“…Interestingly, differences in the mode of action have been described between individual platinum‐derived agents: cisplatin and carboplatin cause DNA cross‐linking and induce a DNA damage response, while oxaliplatin kills tumor cells by inducing ribosome biogenesis stress 51 . An increased sensitivity of patient‐derived cell lines and PDX models with HRD to platin derivates has been demonstrated 38 . In the whole‐genome sequencing study discussed above, hints for an association of unstable genome PDACs with successful platinum response were found, but this was based on only eight patients 36 .…”

Multi-omics consensus ensemble refines the classification of muscle-invasive bladder cancer with stratified prognosis, tumour microenvironment and distinct sensitivity to frontline therapies

“…We referred to a published paper and the angiogenesis gene set (https://www.gseamsigdb.org/gsea/msigdb/cards/ANGIOGENESIS) to construct a signature of ten oncogenic pathways, and the GSVA method was harnessed to generate enrichment scores [23]. A total of 21 replication stress signatures were retrieved from the literature, and single-sample gene set enrichment analysis (ssGSEA) was performed to quantify the enrichment level [24]. Two subtypes of replication stress were identified by hierarchical clustering.…”