TY - JOUR
T1 - Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer
AU - Glasgow Precision Oncology Laboratory,
AU - Glasgow Precision Oncology Laboratory,
AU - Australian Pancreatic Cancer Genome Initiative
AU - Dreyer, Stephan B.
AU - Upstill-Goddard, Rosie
AU - Paulus-Hock, Viola
AU - Paris, Clara
AU - Lampraki, Eirini Maria
AU - Dray, Eloise
AU - Serrels, Bryan
AU - Caligiuri, Giuseppina
AU - Rebus, Selma
AU - Plenker, Dennis
AU - Galluzzo, Zachary
AU - Brunton, Holly
AU - Cunningham, Richard
AU - Tesson, Mathias
AU - Nourse, Craig
AU - Bailey, Ulla Maja
AU - Jones, Marc D.
AU - Moran-Jones, Kim
AU - Wright, Derek W.
AU - Duthie, Fraser
AU - Oien, Karin
AU - Evers, Lisa
AU - McKay, Colin J.
AU - McGregor, Grant A.
AU - Gulati, Aditi
AU - Brough, Rachel
AU - Bajrami, Ilirjana
AU - Pettitt, Stephan
AU - Dziubinski, Michele L.
AU - Candido, Juliana
AU - Balkwill, Frances
AU - Barry, Simon T.
AU - Grützmann, Robert
AU - Rahib, Lola
AU - Allison, Sarah
AU - Bailey, Peter J.
AU - Biankin, Andrew V.
AU - Beraldi, Dario
AU - Cameron, Euan
AU - Chang, David K.
AU - Cooke, Susanna L.
AU - Grimwood, Paul
AU - Kelly, Shane
AU - Marshall, John
AU - Martin, Sancha
AU - McDade, Brian
AU - Eshleman, James R.
AU - Hruban, Ralph H.
AU - Schulick, Richard D.
AU - Wolfgang, Christopher L.
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - DNA Damage Response
KW - Pancreatic Cancer
KW - Personalized Medicine
KW - Replication Stress
UR - http://www.scopus.com/inward/record.url?scp=85097475066&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097475066&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2020.09.043
DO - 10.1053/j.gastro.2020.09.043
M3 - Article
C2 - 33039466
AN - SCOPUS:85097475066
SN - 0016-5085
VL - 160
SP - 362-377.e13
JO - Gastroenterology
JF - Gastroenterology
IS - 1
ER -