Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

被引：15

作者：

Schmitt, Anna ^{[1
]}

Feldmann, Georg ^{[2
,3
]}

Zander, Thomas ^{[1
,3
]}

Reinhardt, H. Christian ^{[1
,3
,4
,5
]}

机构：

[1] Univ Hosp Cologne, Clin Internal Med 1, Weyertal 115B, D-50937 Cologne, Germany

[2] Univ Hosp Bonn, Dept Internal Med 3, Bonn, Germany

[3] Ctr Integrated Oncol CIO Cologne Bonn, Cologne, Germany

[4] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, Cologne, Germany

[5] Univ Cologne, Ctr Mol Med Cologne, Cologne, Germany

来源：

ONCOLOGY RESEARCH AND TREATMENT | 2018年 / 41卷 / 10期

关键词：

Pancreatic ductal adenocarcinoma; DNA damage response; Metastatic disease; SYNTHETIC LETHAL INTERACTION; STRAND BREAK REPAIR; HOMOLOGOUS RECOMBINATION; STK33; KINASE; GERMLINE MUTATIONS; ATM DEFICIENCY; MEK INHIBITION; CANCER; PATHWAYS; BRCA;

D O I：

10.1159/000493401

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Pancreatic cancer is one of the most common causes of cancer-related mortality in the Western world and pancreatic ductal adenocarcinoma (PDAC) is by far the most common pancreatic cancer entity. Locally advanced or metastatic PDAC remains a major clinical challenge, and the prognosis of affected patients is dismal despite substantial research efforts in this area. Recent large-scale genomic analyses of PDAC revealed that KRAS is the most frequently mutated driver gene in this entity. In addition, a relatively large proportion of PDAC patients displays germline variants in genes involved in DNA repair, particularly DNA double-strand repair. Similarly, a sizable fraction of sporadic PDAC cases harbor mutations in genome maintenance genes, such as BRCA1, BRCA2, and ATM. While direct targeting of oncogenic KRAS is currently not possible in the clinical setting, these defects in DNA repair may open new therapeutic avenues. Here, we discuss the potential use of compounds that interfere with DNA repair and genome maintenance mechanisms for the treatment of PDAC. We particularly focus on the genotype-tailored use of compounds, such as PARP inhibitors, as well as ATR- and DNA-protein kinase catalytic subunit (PKcs) inhibitors. (C) 2018 S. Karger GmbH, Freiburg.

引用

页码：619 / 625

页数：7

共 94 条

[1] Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma [J].

Aguirre, Andrew J. ;

Hruban, Ralph H. ;

Raphael, Benjamin J. .

CANCER CELL, 2017, 32 (02) :185-+

[2] Germline BRCA1 mutations predispose to pancreatic adenocarcinoma [J].

Al-Sukhni, Wigdan ;

Rothenmund, Heidi ;

Borgida, Ayelet Eppel ;

Zogopoulos, George ;

O'Shea, Anne-Marie ;

Pollett, Aaron ;

Gallinger, Steven .

HUMAN GENETICS, 2008, 124 (03) :271-278

[3] Signatures of mutational processes in human cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Aparicio, Samuel A. J. R. ;

Behjati, Sam ;

Biankin, Andrew V. ;

Bignell, Graham R. ;

Bolli, Niccolo ;

Borg, Ake ;

Borresen-Dale, Anne-Lise ;

Boyault, Sandrine ;

Burkhardt, Birgit ;

Butler, Adam P. ;

Caldas, Carlos ;

Davies, Helen R. ;

Desmedt, Christine ;

Eils, Roland ;

Eyfjord, Jorunn Erla ;

Foekens, John A. ;

Greaves, Mel ;

Hosoda, Fumie ;

Hutter, Barbara ;

Ilicic, Tomislav ;

Imbeaud, Sandrine ;

Imielinsk, Marcin ;

Jaeger, Natalie ;

Jones, David T. W. ;

Jones, David ;

Knappskog, Stian ;

Kool, Marcel ;

Lakhani, Sunil R. ;

Lopez-Otin, Carlos ;

Martin, Sancha ;

Munshi, Nikhil C. ;

Nakamura, Hiromi ;

Northcott, Paul A. ;

Pajic, Marina ;

Papaemmanuil, Elli ;

Paradiso, Angelo ;

Pearson, John V. ;

Puente, Xose S. ;

Raine, Keiran ;

Ramakrishna, Manasa ;

Richardson, Andrea L. ;

Richter, Julia ;

Rosenstiel, Philip ;

Schlesner, Matthias ;

Schumacher, Ton N. ;

Span, Paul N. ;

Teague, Jon W. .

NATURE, 2013, 500 (7463) :415-+

[4]

[Anonymous], 2013, SCI TRANSL MED

[5]

[Anonymous], KREBS DEUTSCHLAND 20

[6] 5-Fluorouracil/Leucovorin Combined with Irinotecan and Oxaliplatin (FOLFIRINOX) as Second-Line Chemotherapy in Patients with Metastatic Pancreatic Adenocarcinoma [J].

Assaf, Elias ;

Verlinde-Carvalho, Muriel ;

Delbaldo, Catherine ;

Grenier, Julien ;

Sellam, Zineb ;

Pouessel, Damien ;

Bouaita, Linda ;

Baumgaertner, Isabelle ;

Sobhani, Iradj ;

Tayar, Claude ;

Paul, Muriel ;

Culine, Stephane .

ONCOLOGY, 2011, 80 (5-6) :301-306

[7] STK33 Kinase Activity Is Nonessential in KRAS-Dependent Cancer Cells [J].

Babij, Carol ;

Zhang, Yihong ;

Kurzeja, Robert J. ;

Munzli, Anke ;

Shehabeldin, Amro ;

Fernando, Manory ;

Quon, Kim ;

Kassner, Paul D. ;

Ruefli-Brasse, Astrid A. ;

Watson, Vivienne J. ;

Fajardo, Flordeliza ;

Jackson, Angela ;

Zondlo, James ;

Sun, Yu ;

Ellison, Aaron R. ;

Plewa, Cherylene A. ;

San Miguel, Tisha ;

Robinson, John ;

McCarter, John ;

Schwandner, Ralf ;

Judd, Ted ;

Carnahan, Josette ;

Dussault, Isabelle .

CANCER RESEARCH, 2011, 71 (17) :5818-5826

[8] Genomic analyses identify molecular subtypes of pancreatic cancer [J].

Bailey, Peter ;

Chang, David K. ;

Nones, Katia ;

Johns, Amber L. ;

Patch, Ann-Marie ;

Gingras, Marie-Claude ;

Miller, David K. ;

Christ, Angelika N. ;

Bruxner, Tim J. C. ;

Quinn, Michael C. ;

Nourse, Craig ;

Murtaugh, L. Charles ;

Harliwong, Ivon ;

Idrisoglu, Senel ;

Manning, Suzanne ;

Nourbakhsh, Ehsan ;

Wani, Shivangi ;

Fink, Lynn ;

Holmes, Oliver ;

Chin, Vencssa ;

Anderson, Matthew J. ;

Kazakoff, Stephen ;

Leonard, Conrad ;

Newell, Felicity ;

Waddell, Nick ;

Wood, Scott ;

Xu, Qinying ;

Wilson, Peter J. ;

Cloonan, Nicole ;

Kassahn, Karin S. ;

Taylor, Darrin ;

Quek, Kelly ;

Robertson, Alan ;

Pantano, Lorena ;

Mincarelli, Laura ;

Sanchez, Luis N. ;

Evers, Lisa ;

Wu, Jianmin ;

Pinese, Mark ;

Cowley, Mark J. ;

Jones, Marc D. ;

Colvin, Emily K. ;

Nagrial, Adnan M. ;

Humphrey, Emily S. ;

Chantrill, Lorraine A. ;

Mawson, Amanda ;

Humphris, Jeremy ;

Chou, Angela ;

Pajic, Marina ;

Scarlett, Christopher J. .

NATURE, 2016, 531 (7592) :47-+

[9] Familial pancreatic cancer-current knowledge [J].

Bartsch, Detlef K. ;

Gress, Thomas M. ;

Langer, Peter .

NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, 2012, 9 (08) :445-453

[10] Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

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