Centre for Cancer Research - Research Publications

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Author: Christophi, Christopher × Author: Grimmond, Sean × Author: Nikfarjam, Mehrdad × End date: 2021 × Start date: 2020 × Type: Journal Article ×

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    Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer
    Dreyer, SB ; Upstill-Goddard, R ; Paulus-Hock, V ; Paris, C ; Lampraki, E-M ; Dray, E ; Serrels, B ; Caligiuri, G ; Rebus, S ; Plenker, D ; Galluzzo, Z ; Brunton, H ; Cunningham, R ; Tesson, M ; Nourse, C ; Bailey, U-M ; Jones, M ; Moran-Jones, K ; Wright, DW ; Duthie, F ; Oien, K ; Evers, L ; McKay, CJ ; McGregor, GA ; Gulati, A ; Brough, R ; Bajrami, I ; Pettitt, S ; Dziubinski, ML ; Candido, J ; Balkwill, F ; Barry, ST ; Grutzmann, R ; Rahib, L ; Johns, A ; Pajic, M ; Froeling, FEM ; Beer, P ; Musgrove, EA ; Petersen, GM ; Ashworth, A ; Frame, MC ; Crawford, HC ; Simeone, DM ; Lord, C ; Mukhopadhyay, D ; Pilarsky, C ; Tuveson, DA ; Cooke, SL ; Jamieson, NB ; Morton, JP ; Sansom, OJ ; Bailey, PJ ; Biankin, A ; Chang, DK (W B SAUNDERS CO-ELSEVIER INC, 2021-01)
    BACKGROUND & AIMS: 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. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. METHODS: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. RESULTS: 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, cosegregates with response to platinum (P < .001) and PARP inhibitor therapy (P < .001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P < .018) and WEE1 inhibitor (P < .029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < .001) but was not associated with DDR deficiency. CONCLUSIONS: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.
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    HNF4A and GATA6 Loss Reveals Therapeutically Actionable Subtypes in Pancreatic Cancer
    Brunton, H ; Caligiuri, G ; Cunningham, R ; Upstill-Goddard, R ; Bailey, U-M ; Garner, IM ; Nourse, C ; Dreyer, S ; Jones, M ; Moran-Jones, K ; Wright, DW ; Paulus-Hock, V ; Nixon, C ; Thomson, G ; Jamieson, NB ; McGregor, GA ; Evers, L ; McKay, CJ ; Gulati, A ; Brough, R ; Bajrami, I ; Pettitt, SJ ; Dziubinski, ML ; Barry, ST ; Gruetzmann, R ; Brown, R ; Curry, E ; Pajic, M ; Musgrove, EA ; Petersen, GM ; Shanks, E ; Ashworth, A ; Crawford, HC ; Simeone, DM ; Froeling, FEM ; Lord, CJ ; Mukhopadhyay, D ; Pilarsky, C ; Grimmond, SE ; Morton, JP ; Sansom, OJ ; Chang, DK ; Bailey, PJ ; Biankin, A (CELL PRESS, 2020-05-12)
    Pancreatic ductal adenocarcinoma (PDAC) can be divided into transcriptomic subtypes with two broad lineages referred to as classical (pancreatic) and squamous. We find that these two subtypes are driven by distinct metabolic phenotypes. Loss of genes that drive endodermal lineage specification, HNF4A and GATA6, switch metabolic profiles from classical (pancreatic) to predominantly squamous, with glycogen synthase kinase 3 beta (GSK3β) a key regulator of glycolysis. Pharmacological inhibition of GSK3β results in selective sensitivity in the squamous subtype; however, a subset of these squamous patient-derived cell lines (PDCLs) acquires rapid drug tolerance. Using chromatin accessibility maps, we demonstrate that the squamous subtype can be further classified using chromatin accessibility to predict responsiveness and tolerance to GSK3β inhibitors. Our findings demonstrate that distinct patterns of chromatin accessibility can be used to identify patient subgroups that are indistinguishable by gene expression profiles, highlighting the utility of chromatin-based biomarkers for patient selection in the treatment of PDAC.