Targeting DNA damage response and replication stress in pancreatic cancer

Stephan B. Dreyer; Rosie Upstill-Goddard; Viola Paulus-Hock; Clara Paris; Eirini-Maria Lampraki; Eloise Dray; Bryan Serrels; Giuseppina Caligiuri; Selma Rebus; Dennis Plenker; Zachary Galluzzo; Holly Brunton; Richard Cunningham; Mathias Tesson; Craig Nourse; Ulla-Maja Bailey; Marc Jones; Kim Moran-Jones; Derek W. Wright; Fraser Duthie; Karin Oien; Lisa Evers; Colin J. McKay; Grant A. McGregor; Aditi Gulati; Rachel Brough; Ilirjana Bajrami; Stephan Pettitt; Michele L. Dziubinski; Juliana Candido; Frances Balkwill; Simon T. Barry; Robert Grützmann; Lola Rahib; null Glasgow Precision Oncology Laboratory; null Australian Pancreatic Cancer Genome Initiative; Neil D. Merrett; Amber Johns; Marina Pajic; Fieke E. M. Froeling; Phillip Beer; Elizabeth A. Musgrove; Gloria M. Petersen; Alan Ashworth; Margaret C. Frame; Howard C. Crawford; Diane M. Simeone; Chris Lord; Debabrata Mukhopadhyay; Christian Pilarsky; David A. Tuveson; Susanna L. Cooke; Nigel B. Jamieson; Jennifer P. Morton; Owen J. Sansom; Peter J. Bailey; Andrew V. Biankin; David K. Chang

doi:10.1053/j.gastro.2020.09.043

Targeting DNA damage response and replication stress in pancreatic cancer

Stephan B. Dreyer, Rosie Upstill-Goddard, Viola Paulus-Hock, Clara Paris, Eirini-Maria Lampraki, Eloise Dray, Bryan Serrels, Giuseppina Caligiuri, Selma Rebus, Dennis Plenker, Zachary Galluzzo, Holly Brunton, Richard Cunningham, Mathias Tesson, Craig Nourse, Ulla-Maja Bailey, Marc Jones, Kim Moran-Jones, Derek W. Wright, Fraser DuthieKarin Oien, Lisa Evers, Colin J. McKay, Grant A. McGregor, Aditi Gulati, Rachel Brough, Ilirjana Bajrami, Stephan Pettitt, Michele L. Dziubinski, Juliana Candido, Frances Balkwill, Simon T. Barry, Robert Grützmann, Lola Rahib, Glasgow Precision Oncology Laboratory, Australian Pancreatic Cancer Genome Initiative, Neil D. Merrett, Amber Johns, Marina Pajic, Fieke E. M. Froeling, Phillip Beer, Elizabeth A. Musgrove, Gloria M. Petersen, Alan Ashworth, Margaret C. Frame, Howard C. Crawford, Diane M. Simeone, Chris Lord, Debabrata Mukhopadhyay, Christian Pilarsky, David A. Tuveson, Susanna L. Cooke, Nigel B. Jamieson, Jennifer P. Morton, Owen J. Sansom, Peter J. Bailey, Andrew V. Biankin, David K. Chang

Western Sydney University

Research output: Contribution to journal › Article › peer-review

90 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	362-377
Number of pages	16
Journal	Gastroenterology
Volume	160
Issue number	1
DOIs	https://doi.org/10.1053/j.gastro.2020.09.043
Publication status	Published - 2021

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10.1053/j.gastro.2020.09.043

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Dreyer, S. B., 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, D. W., ... Chang, D. K. (2021). Targeting DNA damage response and replication stress in pancreatic cancer. Gastroenterology, 160(1), 362-377. https://doi.org/10.1053/j.gastro.2020.09.043

@article{94b74e2cfab749b29950650ea006ee28,

title = "Targeting DNA damage response and replication stress in pancreatic cancer",

abstract = "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.",

author = "Dreyer, {Stephan B.} and Rosie Upstill-Goddard and Viola Paulus-Hock and Clara Paris and Eirini-Maria Lampraki and Eloise Dray and Bryan Serrels and Giuseppina Caligiuri and Selma Rebus and Dennis Plenker and Zachary Galluzzo and Holly Brunton and Richard Cunningham and Mathias Tesson and Craig Nourse and Ulla-Maja Bailey and Marc Jones and Kim Moran-Jones and Wright, {Derek W.} and Fraser Duthie and Karin Oien and Lisa Evers and McKay, {Colin J.} and McGregor, {Grant A.} and Aditi Gulati and Rachel Brough and Ilirjana Bajrami and Stephan Pettitt and Dziubinski, {Michele L.} and Juliana Candido and Frances Balkwill and Barry, {Simon T.} and Robert Gr{\"u}tzmann and Lola Rahib and {Glasgow Precision Oncology Laboratory} and {Australian Pancreatic Cancer Genome Initiative} and Merrett, {Neil D.} and Amber Johns and Marina Pajic and Froeling, {Fieke E. M.} and Phillip Beer and Musgrove, {Elizabeth A.} and Petersen, {Gloria M.} and Alan Ashworth and Frame, {Margaret C.} and Crawford, {Howard C.} and Simeone, {Diane M.} and Chris Lord and Debabrata Mukhopadhyay and Christian Pilarsky and Tuveson, {David A.} and Cooke, {Susanna L.} and Jamieson, {Nigel B.} and Morton, {Jennifer P.} and Sansom, {Owen J.} and Bailey, {Peter J.} and Biankin, {Andrew V.} and Chang, {David K.}",

year = "2021",

doi = "10.1053/j.gastro.2020.09.043",

language = "English",

volume = "160",

pages = "362--377",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "Elsevier",

number = "1",

}

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, Grützmann, R, Rahib, L, Glasgow Precision Oncology Laboratory, Australian Pancreatic Cancer Genome Initiative, , Merrett, ND, 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, AV & Chang, DK 2021, 'Targeting DNA damage response and replication stress in pancreatic cancer', Gastroenterology, vol. 160, no. 1, pp. 362-377. https://doi.org/10.1053/j.gastro.2020.09.043

TY - JOUR

T1 - Targeting DNA damage response and replication stress in pancreatic cancer

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

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 - Glasgow Precision Oncology Laboratory, null

AU - Australian Pancreatic Cancer Genome Initiative, null

AU - Merrett, Neil D.

AU - Johns, Amber

AU - Pajic, Marina

AU - Froeling, Fieke E. M.

AU - Beer, Phillip

AU - Musgrove, Elizabeth A.

AU - Petersen, Gloria M.

AU - Ashworth, Alan

AU - Frame, Margaret C.

AU - Crawford, Howard C.

AU - Simeone, Diane M.

AU - Lord, Chris

AU - Mukhopadhyay, Debabrata

AU - Pilarsky, Christian

AU - Tuveson, David A.

AU - Cooke, Susanna L.

AU - Jamieson, Nigel B.

AU - Morton, Jennifer P.

AU - Sansom, Owen J.

AU - Bailey, Peter J.

AU - Biankin, Andrew V.

AU - Chang, David K.

PY - 2021

Y1 - 2021

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.

UR - http://hdl.handle.net/1959.7/uws:61437

U2 - 10.1053/j.gastro.2020.09.043

DO - 10.1053/j.gastro.2020.09.043

M3 - Article

SN - 0016-5085

VL - 160

SP - 362

EP - 377

JO - Gastroenterology

JF - Gastroenterology

IS - 1

ER -

Targeting DNA damage response and replication stress in pancreatic cancer

Abstract

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