Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer
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 therapeu...
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| Veröffentlicht in: | Gastroenterology (New York, N.Y. 1943) N.Y. 1943), 2021-01, Vol.160 (1), p.362-377.e13 |
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| creator | Dreyer, Stephan B. Upstill-Goddard, Rosie Paulus-Hock, Viola Paris, Clara Dray, Eloise Serrels, Bryan Caligiuri, Giuseppina Caligiuri, Giuseppina Rebus, Selma Plenker, Dennis Brunton, Holly Wright, Derek W. McKay, Colin J. Gulati, Aditi Pettitt, Stephan Bailey, Peter J. Chang, David K. Cooke, Susanna L. Dreyer, Stephan Kelly, Shane Marshall, John McDade, Brian Nourse, Craig Paulus-Hock, Viola Westwood, Paul Biankin, Andrew V. Brancato, Mary-Anne L. Chin, Venessa T. Cowley, Mark J. Mead, R. Scott Nagrial, Adnan M. Pettit, Jessica Pinese, Mark Rooman, Ilse Tao, Jiang DiPietro, Renee Watson, Clare Wong, Rachel Giry-Laterriere, Marc Grimmond, Sean M. Waddell, Nicola Kassahn, Karin S. Patch, Ann-Marie Idrisoglu, Senel Nourbakhsh, Ehsan Wani, Shivangi Taylor, Darrin Wood, Scott Fink, J. Lynn Bruxner, Tim Cloonan, Nicole Newell, Felicity Pearson, John V. Bailey, Peter Kazakoff, Stephen Samra, Jaswinder S. Gill, Anthony J. Pavlakis, Nick Asghari, Ray Merrett, Neil D. Cosman, Peter H. Ismail, Kasim McLeod, Duncan James, Virginia Kench, James G. Cooper, Caroline L. Sandroussi, Charbel Gallagher, James Texler, Michael Forest, Cindy Ballal, Mo DeBoer, Bastiaan Chai, Ming Worthley, Chris Tan, Chuan P. Martin, Patrick Chiang, Amy Yeung, Shinn Hatzifotis, Michael Christophi, Christopher Biobank, Victorian Cancer Hruban, Ralph H. Iacobuzio-Donahue, Christine A. Schulick, Richard D. Morgan, Richard A. Hodgin, Mary Scarpa, Aldo Lawlor, Rita T. Biankin, Andrew V. Grimmond, Sean M. Nourse, Craig Johns, Amber Pajic, Marina Frame, Margaret C. Crawford, Howard C. Pilarsky, Christian Morton, Jennifer P. Sansom, Owen J. Bailey, Peter J. Chang, David K. |
| description | 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.
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.
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.
Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.
[Display omitted] |
| doi_str_mv | 10.1053/j.gastro.2020.09.043 |
| format | Article |
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Scott ; Nagrial, Adnan M. ; Pettit, Jessica ; Pinese, Mark ; Rooman, Ilse ; Tao, Jiang ; DiPietro, Renee ; Watson, Clare ; Wong, Rachel ; Giry-Laterriere, Marc ; Grimmond, Sean M. ; Waddell, Nicola ; Kassahn, Karin S. ; Patch, Ann-Marie ; Idrisoglu, Senel ; Nourbakhsh, Ehsan ; Wani, Shivangi ; Taylor, Darrin ; Wood, Scott ; Fink, J. Lynn ; Bruxner, Tim ; Cloonan, Nicole ; Newell, Felicity ; Pearson, John V. ; Bailey, Peter ; Kazakoff, Stephen ; Samra, Jaswinder S. ; Gill, Anthony J. ; Pavlakis, Nick ; Asghari, Ray ; Merrett, Neil D. ; Cosman, Peter H. ; Ismail, Kasim ; McLeod, Duncan ; James, Virginia ; Kench, James G. ; Cooper, Caroline L. ; Sandroussi, Charbel ; Gallagher, James ; Texler, Michael ; Forest, Cindy ; Ballal, Mo ; DeBoer, Bastiaan ; Chai, Ming ; Worthley, Chris ; Tan, Chuan P. ; Martin, Patrick ; Chiang, Amy ; Yeung, Shinn ; Hatzifotis, Michael ; Christophi, Christopher ; Biobank, Victorian Cancer ; Hruban, Ralph H. ; Iacobuzio-Donahue, Christine A. ; Schulick, Richard D. ; Morgan, Richard A. ; Hodgin, Mary ; Scarpa, Aldo ; Lawlor, Rita T. ; Biankin, Andrew V. ; Grimmond, Sean M. ; Nourse, Craig ; Johns, Amber ; Pajic, Marina ; Frame, Margaret C. ; Crawford, Howard C. ; Pilarsky, Christian ; Morton, Jennifer P. ; Sansom, Owen J. ; Bailey, Peter J. ; Chang, David K.</creator><creatorcontrib>Dreyer, Stephan B. ; Upstill-Goddard, Rosie ; Paulus-Hock, Viola ; Paris, Clara ; Dray, Eloise ; Serrels, Bryan ; Caligiuri, Giuseppina ; Caligiuri, Giuseppina ; Rebus, Selma ; Plenker, Dennis ; Brunton, Holly ; Wright, Derek W. ; McKay, Colin J. ; Gulati, Aditi ; Pettitt, Stephan ; Bailey, Peter J. ; Chang, David K. ; Cooke, Susanna L. ; Dreyer, Stephan ; Kelly, Shane ; Marshall, John ; McDade, Brian ; Nourse, Craig ; Paulus-Hock, Viola ; Westwood, Paul ; Biankin, Andrew V. ; Brancato, Mary-Anne L. ; Chin, Venessa T. ; Cowley, Mark J. ; Mead, R. Scott ; Nagrial, Adnan M. ; Pettit, Jessica ; Pinese, Mark ; Rooman, Ilse ; Tao, Jiang ; DiPietro, Renee ; Watson, Clare ; Wong, Rachel ; Giry-Laterriere, Marc ; Grimmond, Sean M. ; Waddell, Nicola ; Kassahn, Karin S. ; Patch, Ann-Marie ; Idrisoglu, Senel ; Nourbakhsh, Ehsan ; Wani, Shivangi ; Taylor, Darrin ; Wood, Scott ; Fink, J. Lynn ; Bruxner, Tim ; Cloonan, Nicole ; Newell, Felicity ; Pearson, John V. ; Bailey, Peter ; Kazakoff, Stephen ; Samra, Jaswinder S. ; Gill, Anthony J. ; Pavlakis, Nick ; Asghari, Ray ; Merrett, Neil D. ; Cosman, Peter H. ; Ismail, Kasim ; McLeod, Duncan ; James, Virginia ; Kench, James G. ; Cooper, Caroline L. ; Sandroussi, Charbel ; Gallagher, James ; Texler, Michael ; Forest, Cindy ; Ballal, Mo ; DeBoer, Bastiaan ; Chai, Ming ; Worthley, Chris ; Tan, Chuan P. ; Martin, Patrick ; Chiang, Amy ; Yeung, Shinn ; Hatzifotis, Michael ; Christophi, Christopher ; Biobank, Victorian Cancer ; Hruban, Ralph H. ; Iacobuzio-Donahue, Christine A. ; Schulick, Richard D. ; Morgan, Richard A. ; Hodgin, Mary ; Scarpa, Aldo ; Lawlor, Rita T. ; Biankin, Andrew V. ; Grimmond, Sean M. ; Nourse, Craig ; Johns, Amber ; Pajic, Marina ; Frame, Margaret C. ; Crawford, Howard C. ; Pilarsky, Christian ; Morton, Jennifer P. ; Sansom, Owen J. ; Bailey, Peter J. ; Chang, David K. ; Glasgow Precision Oncology Laboratory ; Australian Pancreatic Cancer Genome Initiative</creatorcontrib><description>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.
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.
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.
Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.
[Display omitted]</description><identifier>ISSN: 0016-5085</identifier><identifier>EISSN: 1528-0012</identifier><identifier>DOI: 10.1053/j.gastro.2020.09.043</identifier><identifier>PMID: 33039466</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenocarcinoma - genetics ; Adenocarcinoma - pathology ; Adenocarcinoma - therapy ; Biomarkers ; Cell Culture Techniques ; Cell Line, Tumor ; DNA Damage - genetics ; DNA Damage Response ; DNA Repair - genetics ; DNA Replication - genetics ; Humans ; Molecular Targeted Therapy ; Organoids ; Original Research ; Pancreatic Cancer ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - pathology ; Pancreatic Neoplasms - therapy ; Personalized Medicine ; Replication Stress ; Xenograft Model Antitumor Assays</subject><ispartof>Gastroenterology (New York, N.Y. 1943), 2021-01, Vol.160 (1), p.362-377.e13</ispartof><rights>2021 The Authors</rights><rights>Copyright © 2021 The Authors. Published by Elsevier Inc. 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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.
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.
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.
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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Saunders</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6134-2096</orcidid><orcidid>https://orcid.org/0000-0003-3313-3857</orcidid><orcidid>https://orcid.org/0000-0002-7968-3283</orcidid><orcidid>https://orcid.org/0000-0002-0955-0346</orcidid><orcidid>https://orcid.org/0000-0003-0411-4497</orcidid><orcidid>https://orcid.org/0000-0002-2666-0934</orcidid><orcidid>https://orcid.org/0000-0002-8653-8164</orcidid><orcidid>https://orcid.org/0000-0002-5688-8542</orcidid><orcidid>https://orcid.org/0000-0001-8825-810X</orcidid><orcidid>https://orcid.org/0000-0002-3078-8359</orcidid><orcidid>https://orcid.org/0000-0003-3424-7039</orcidid><orcidid>https://orcid.org/0000-0003-0314-0634</orcidid></search><sort><creationdate>202101</creationdate><title>Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer</title><author>Dreyer, Stephan B. ; Upstill-Goddard, Rosie ; Paulus-Hock, Viola ; Paris, Clara ; Dray, Eloise ; Serrels, Bryan ; Caligiuri, Giuseppina ; Caligiuri, Giuseppina ; Rebus, Selma ; Plenker, Dennis ; Brunton, Holly ; Wright, Derek W. ; McKay, Colin J. ; Gulati, Aditi ; Pettitt, Stephan ; Bailey, Peter J. ; Chang, David K. ; Cooke, Susanna L. ; Dreyer, Stephan ; Kelly, Shane ; Marshall, John ; McDade, Brian ; Nourse, Craig ; Paulus-Hock, Viola ; Westwood, Paul ; Biankin, Andrew V. ; Brancato, Mary-Anne L. ; Chin, Venessa T. ; Cowley, Mark J. ; Mead, R. Scott ; Nagrial, Adnan M. ; Pettit, Jessica ; Pinese, Mark ; Rooman, Ilse ; Tao, Jiang ; DiPietro, Renee ; Watson, Clare ; Wong, Rachel ; Giry-Laterriere, Marc ; Grimmond, Sean M. ; Waddell, Nicola ; Kassahn, Karin S. ; Patch, Ann-Marie ; Idrisoglu, Senel ; Nourbakhsh, Ehsan ; Wani, Shivangi ; Taylor, Darrin ; Wood, Scott ; Fink, J. Lynn ; Bruxner, Tim ; Cloonan, Nicole ; Newell, Felicity ; Pearson, John V. ; Bailey, Peter ; Kazakoff, Stephen ; Samra, Jaswinder S. ; Gill, Anthony J. ; Pavlakis, Nick ; Asghari, Ray ; Merrett, Neil D. ; Cosman, Peter H. ; Ismail, Kasim ; McLeod, Duncan ; James, Virginia ; Kench, James G. ; Cooper, Caroline L. ; Sandroussi, Charbel ; Gallagher, James ; Texler, Michael ; Forest, Cindy ; Ballal, Mo ; DeBoer, Bastiaan ; Chai, Ming ; Worthley, Chris ; Tan, Chuan P. ; Martin, Patrick ; Chiang, Amy ; Yeung, Shinn ; Hatzifotis, Michael ; Christophi, Christopher ; Biobank, Victorian Cancer ; Hruban, Ralph H. ; Iacobuzio-Donahue, Christine A. ; Schulick, Richard D. ; Morgan, Richard A. ; Hodgin, Mary ; Scarpa, Aldo ; Lawlor, Rita T. ; Biankin, Andrew V. ; Grimmond, Sean M. ; Nourse, Craig ; Johns, Amber ; Pajic, Marina ; Frame, Margaret C. ; Crawford, Howard C. ; Pilarsky, Christian ; Morton, Jennifer P. ; Sansom, Owen J. ; Bailey, Peter J. ; Chang, David K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c514t-aa704ffb4a0b110fc4e1897d59796da38962d9fbf6d4ac8c0864f8efca6064fd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adenocarcinoma - genetics</topic><topic>Adenocarcinoma - pathology</topic><topic>Adenocarcinoma - therapy</topic><topic>Biomarkers</topic><topic>Cell Culture Techniques</topic><topic>Cell Line, Tumor</topic><topic>DNA Damage - genetics</topic><topic>DNA Damage Response</topic><topic>DNA Repair - genetics</topic><topic>DNA Replication - genetics</topic><topic>Humans</topic><topic>Molecular Targeted Therapy</topic><topic>Organoids</topic><topic>Original Research</topic><topic>Pancreatic Cancer</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Pancreatic Neoplasms - therapy</topic><topic>Personalized Medicine</topic><topic>Replication Stress</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dreyer, Stephan B.</creatorcontrib><creatorcontrib>Upstill-Goddard, Rosie</creatorcontrib><creatorcontrib>Paulus-Hock, Viola</creatorcontrib><creatorcontrib>Paris, Clara</creatorcontrib><creatorcontrib>Dray, Eloise</creatorcontrib><creatorcontrib>Serrels, Bryan</creatorcontrib><creatorcontrib>Caligiuri, Giuseppina</creatorcontrib><creatorcontrib>Caligiuri, Giuseppina</creatorcontrib><creatorcontrib>Rebus, Selma</creatorcontrib><creatorcontrib>Plenker, Dennis</creatorcontrib><creatorcontrib>Brunton, Holly</creatorcontrib><creatorcontrib>Wright, Derek W.</creatorcontrib><creatorcontrib>McKay, Colin J.</creatorcontrib><creatorcontrib>Gulati, Aditi</creatorcontrib><creatorcontrib>Pettitt, Stephan</creatorcontrib><creatorcontrib>Bailey, Peter J.</creatorcontrib><creatorcontrib>Chang, David K.</creatorcontrib><creatorcontrib>Cooke, Susanna L.</creatorcontrib><creatorcontrib>Dreyer, Stephan</creatorcontrib><creatorcontrib>Kelly, Shane</creatorcontrib><creatorcontrib>Marshall, John</creatorcontrib><creatorcontrib>McDade, Brian</creatorcontrib><creatorcontrib>Nourse, Craig</creatorcontrib><creatorcontrib>Paulus-Hock, Viola</creatorcontrib><creatorcontrib>Westwood, Paul</creatorcontrib><creatorcontrib>Biankin, Andrew V.</creatorcontrib><creatorcontrib>Brancato, Mary-Anne L.</creatorcontrib><creatorcontrib>Chin, Venessa T.</creatorcontrib><creatorcontrib>Cowley, Mark J.</creatorcontrib><creatorcontrib>Mead, R. Scott</creatorcontrib><creatorcontrib>Nagrial, Adnan M.</creatorcontrib><creatorcontrib>Pettit, Jessica</creatorcontrib><creatorcontrib>Pinese, Mark</creatorcontrib><creatorcontrib>Rooman, Ilse</creatorcontrib><creatorcontrib>Tao, Jiang</creatorcontrib><creatorcontrib>DiPietro, Renee</creatorcontrib><creatorcontrib>Watson, Clare</creatorcontrib><creatorcontrib>Wong, Rachel</creatorcontrib><creatorcontrib>Giry-Laterriere, Marc</creatorcontrib><creatorcontrib>Grimmond, Sean M.</creatorcontrib><creatorcontrib>Waddell, Nicola</creatorcontrib><creatorcontrib>Kassahn, Karin S.</creatorcontrib><creatorcontrib>Patch, Ann-Marie</creatorcontrib><creatorcontrib>Idrisoglu, Senel</creatorcontrib><creatorcontrib>Nourbakhsh, Ehsan</creatorcontrib><creatorcontrib>Wani, Shivangi</creatorcontrib><creatorcontrib>Taylor, Darrin</creatorcontrib><creatorcontrib>Wood, Scott</creatorcontrib><creatorcontrib>Fink, J. 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Scott</au><au>Nagrial, Adnan M.</au><au>Pettit, Jessica</au><au>Pinese, Mark</au><au>Rooman, Ilse</au><au>Tao, Jiang</au><au>DiPietro, Renee</au><au>Watson, Clare</au><au>Wong, Rachel</au><au>Giry-Laterriere, Marc</au><au>Grimmond, Sean M.</au><au>Waddell, Nicola</au><au>Kassahn, Karin S.</au><au>Patch, Ann-Marie</au><au>Idrisoglu, Senel</au><au>Nourbakhsh, Ehsan</au><au>Wani, Shivangi</au><au>Taylor, Darrin</au><au>Wood, Scott</au><au>Fink, J. Lynn</au><au>Bruxner, Tim</au><au>Cloonan, Nicole</au><au>Newell, Felicity</au><au>Pearson, John V.</au><au>Bailey, Peter</au><au>Kazakoff, Stephen</au><au>Samra, Jaswinder S.</au><au>Gill, Anthony J.</au><au>Pavlakis, Nick</au><au>Asghari, Ray</au><au>Merrett, Neil D.</au><au>Cosman, Peter H.</au><au>Ismail, Kasim</au><au>McLeod, Duncan</au><au>James, Virginia</au><au>Kench, James G.</au><au>Cooper, Caroline L.</au><au>Sandroussi, Charbel</au><au>Gallagher, James</au><au>Texler, Michael</au><au>Forest, Cindy</au><au>Ballal, Mo</au><au>DeBoer, Bastiaan</au><au>Chai, Ming</au><au>Worthley, Chris</au><au>Tan, Chuan P.</au><au>Martin, Patrick</au><au>Chiang, Amy</au><au>Yeung, Shinn</au><au>Hatzifotis, Michael</au><au>Christophi, Christopher</au><au>Biobank, Victorian Cancer</au><au>Hruban, Ralph H.</au><au>Iacobuzio-Donahue, Christine A.</au><au>Schulick, Richard D.</au><au>Morgan, Richard A.</au><au>Hodgin, Mary</au><au>Scarpa, Aldo</au><au>Lawlor, Rita T.</au><au>Biankin, Andrew V.</au><au>Grimmond, Sean M.</au><au>Nourse, Craig</au><au>Johns, Amber</au><au>Pajic, Marina</au><au>Frame, Margaret C.</au><au>Crawford, Howard C.</au><au>Pilarsky, Christian</au><au>Morton, Jennifer P.</au><au>Sansom, Owen J.</au><au>Bailey, Peter J.</au><au>Chang, David K.</au><aucorp>Glasgow Precision Oncology Laboratory</aucorp><aucorp>Australian Pancreatic Cancer Genome Initiative</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer</atitle><jtitle>Gastroenterology (New York, N.Y. 1943)</jtitle><addtitle>Gastroenterology</addtitle><date>2021-01</date><risdate>2021</risdate><volume>160</volume><issue>1</issue><spage>362</spage><epage>377.e13</epage><pages>362-377.e13</pages><issn>0016-5085</issn><eissn>1528-0012</eissn><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. 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.
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.
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.
Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.
[Display omitted]</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>33039466</pmid><doi>10.1053/j.gastro.2020.09.043</doi><orcidid>https://orcid.org/0000-0001-6134-2096</orcidid><orcidid>https://orcid.org/0000-0003-3313-3857</orcidid><orcidid>https://orcid.org/0000-0002-7968-3283</orcidid><orcidid>https://orcid.org/0000-0002-0955-0346</orcidid><orcidid>https://orcid.org/0000-0003-0411-4497</orcidid><orcidid>https://orcid.org/0000-0002-2666-0934</orcidid><orcidid>https://orcid.org/0000-0002-8653-8164</orcidid><orcidid>https://orcid.org/0000-0002-5688-8542</orcidid><orcidid>https://orcid.org/0000-0001-8825-810X</orcidid><orcidid>https://orcid.org/0000-0002-3078-8359</orcidid><orcidid>https://orcid.org/0000-0003-3424-7039</orcidid><orcidid>https://orcid.org/0000-0003-0314-0634</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0016-5085 |
| ispartof | Gastroenterology (New York, N.Y. 1943), 2021-01, Vol.160 (1), p.362-377.e13 |
| issn | 0016-5085 1528-0012 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8167930 |
| source | MEDLINE; Elsevier ScienceDirect Journals; Alma/SFX Local Collection |
| subjects | Adenocarcinoma - genetics Adenocarcinoma - pathology Adenocarcinoma - therapy Biomarkers Cell Culture Techniques Cell Line, Tumor DNA Damage - genetics DNA Damage Response DNA Repair - genetics DNA Replication - genetics Humans Molecular Targeted Therapy Organoids Original Research Pancreatic Cancer Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Pancreatic Neoplasms - therapy Personalized Medicine Replication Stress Xenograft Model Antitumor Assays |
| title | Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer |
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