A Synergistic Interaction between Chk1-and MK2 Inhibitors in KRAS-Mutant Cancer

被引：110

作者：

Dietlein, Felix ^{[1
,2
]}

Kalb, Bastian ^{[1
,2
]}

Jokic, Mladen ^{[1
,2
]}

Noll, Elisa M. ^{[3
,4
]}

Strong, Alexander ^{[5
]}

Tharun, Lars ^{[6
]}

Ozretic, Luka ^{[6
]}

Kuenstlinger, Helen ^{[6
]}

Kambartel, Kato ^{[7
,8
]}

Randerath, Winfried J. ^{[7
,9
]}

Juengst, Christian ^{[2
]}

Schmitt, Anna ^{[1
,2
]}

Torgovnick, Alessandro ^{[1
,2
]}

Richters, Andre ^{[10
]}

Rauh, Daniel ^{[10
]}

Siedek, Florian ^{[11
]}

Persigehl, Thorsten ^{[11
]}

Mauch, Cornelia ^{[12
]}

Bartkova, Jirina ^{[13
,14
,15
]}

Bradley, Allan ^{[5
]}

Sprick, Martin R. ^{[4
]}

Trumpp, Andreas ^{[3
,4
,16
]}

Rad, Roland ^{[17
]}

Saur, Dieter ^{[17
]}

Bartek, Jiri ^{[13
,14
,15
]}

Wolf, Juergen ^{[1
,7
]}

Buettner, Reinhard ^{[6
,7
]}

Thomas, Roman K. ^{[6
,18
]}

Reinhardt, H. Christian ^{[1
,2
]}

机构：

[1] Univ Hosp Cologne, Dept Internal Med, D-50931 Cologne, Germany

[2] Univ Cologne, CECAD, D-50931 Cologne, Germany

[3] Deutsch Krebsforschungszentrum, Div Stem Cells & Canc, D-69120 Heidelberg, Germany

[4] Heidelberg Inst Stem Cell Technol & Expt Med, D-69120 Heidelberg, Germany

[5] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[6] Univ Hosp Cologne, Inst Pathol, D-50937 Cologne, Germany

[7] Univ Hosp Cologne, Network Genom Med, D-50937 Cologne, Germany

[8] Krankenhaus Bethanien Moers, Lungenklin, D-47441 Moers, Germany

[9] Krankenhaus Bethanien Solingen, Klin Pneumol, D-42699 Solingen, Germany

[10] Tech Univ Dortmund, Dept Chem & Biol Chem, D-44227 Dortmund, Germany

[11] Univ Hosp Cologne, Dept Radiol, D-50937 Cologne, Germany

[12] Univ Hosp Cologne, Dept Dermatol, D-50937 Cologne, Germany

[13] Danish Canc Soc Res Ctr, DK-2100 Copenhagen, Denmark

[14] Palacky Univ, Inst Mol & Translat Med, Olomouc 77900, Czech Republic

[15] Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, S-17177 Stockholm, Sweden

[16] German Canc Consortium, D-69120 Heidelberg, Germany

[17] Tech Univ Munich, Klinikum Rechts Isar, Dept Internal Med 2, D-81675 Munich, Germany

[18] Univ Cologne, Fac Med, Dept Translat Gen, D-50931 Cologne, Germany

来源：

CELL | 2015年 / 162卷 / 01期

基金：

新加坡国家研究基金会;

关键词：

CELL-CYCLE; REVEALS; MODEL;

D O I：

10.1016/j.cell.2015.05.053

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell-cycle checkpoint-abrogating Chk1- and MK2 inhibitors, specifically in KRAS- and BRAF-driven cells. Mechanistically, we show that KRAS-mutant cancer displays intrinsic genotoxic stress, leading to tonic Chk1- and MK2 activity. We demonstrate that simultaneous Chk1- and MK2 inhibition leads to mitotic catastrophe in KRAS-mutant cells. This actionable synergistic interaction is validated using xenograft models, as well as distinct Kras- or Braf-driven autochthonous murine cancer models. Lastly, we show that combined checkpoint inhibition induces apoptotic cell death in KRAS- or BRAF-mutant tumor cells directly isolated from patients. These results strongly recommend simultaneous Chk1- and MK2 inhibition as a therapeutic strategy for the treatment of KRAS- or BRAF-driven cancers.

引用

页码：146 / 159

页数：14

共 15 条

[1]

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity [J].

Barretina, Jordi ;

Caponigro, Giordano ;

Stransky, Nicolas ;

Venkatesan, Kavitha ;

Margolin, Adam A. ;

Kim, Sungjoon ;

Wilson, Christopher J. ;

Lehar, Joseph ;

Kryukov, Gregory V. ;

Sonkin, Dmitriy ;

Reddy, Anupama ;

Liu, Manway ;

Murray, Lauren ;

Berger, Michael F. ;

Monahan, John E. ;

Morais, Paula ;

Meltzer, Jodi ;

Korejwa, Adam ;

Jane-Valbuena, Judit ;

Mapa, Felipa A. ;

Thibault, Joseph ;

Bric-Furlong, Eva ;

Raman, Pichai ;

Shipway, Aaron ;

Engels, Ingo H. ;

Cheng, Jill ;

Yu, Guoying K. ;

Yu, Jianjun ;

Aspesi, Peter, Jr. ;

de Silva, Melanie ;

Jagtap, Kalpana ;

Jones, Michael D. ;

Wang, Li ;

Hatton, Charles ;

Palescandolo, Emanuele ;

Gupta, Supriya ;

Mahan, Scott ;

Sougnez, Carrie ;

Onofrio, Robert C. ;

Liefeld, Ted ;

MacConaill, Laura ;

Winckler, Wendy ;

Reich, Michael ;

Li, Nanxin ;

Mesirov, Jill P. ;

Gabriel, Stacey B. ;

Getz, Gad ;

Ardlie, Kristin ;

Chan, Vivien ;

Myer, Vic E. .

NATURE, 2012, 483 (7391) :603-607

[2]

Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints [J].

Bartkova, Jirina ;

Rezaei, Nousin ;

Liontos, Michalis ;

Karakaidos, Panagiotis ;

Kletsas, Dimitris ;

Issaeva, Natalia ;

Vassiliou, Leandros-Vassilios F. ;

Kolettas, Evangelos ;

Niforou, Katerina ;

Zoumpourlis, Vassilis C. ;

Takaoka, Munenori ;

Nakagawa, Hiroshi ;

Tort, Frederic ;

Fugger, Kasper ;

Johansson, Fredrik ;

Sehested, Maxwell ;

Andersen, Claus L. ;

Dyrskjot, Lars ;

Orntoft, Torben ;

Lukas, Jiri ;

Kittas, Christos ;

Helleday, Thomas ;

Halazonetis, Thanos D. ;

Bartek, Jiri ;

Gorgoulis, Vassilis G. .

NATURE, 2006, 444 (7119) :633-637

[3]

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes [J].

Biankin, Andrew V. ;

Waddell, Nicola ;

Kassahn, Karin S. ;

Gingras, Marie-Claude ;

Muthuswamy, Lakshmi B. ;

Johns, Amber L. ;

Miller, David K. ;

Wilson, Peter J. ;

Patch, Ann-Marie ;

Wu, Jianmin ;

Chang, David K. ;

Cowley, Mark J. ;

Gardiner, Brooke B. ;

Song, Sarah ;

Harliwong, Ivon ;

Idrisoglu, Senel ;

Nourse, Craig ;

Nourbakhsh, Ehsan ;

Manning, Suzanne ;

Wani, Shivangi ;

Gongora, Milena ;

Pajic, Marina ;

Scarlett, Christopher J. ;

Gill, Anthony J. ;

Pinho, Andreia V. ;

Rooman, Ilse ;

Anderson, Matthew ;

Holmes, Oliver ;

Leonard, Conrad ;

Taylor, Darrin ;

Wood, Scott ;

Xu, Qinying ;

Nones, Katia ;

Fink, J. Lynn ;

Christ, Angelika ;

Bruxner, Tim ;

Cloonan, Nicole ;

Kolle, Gabriel ;

Newell, Felicity ;

Pinese, Mark ;

Mead, R. Scott ;

Humphris, Jeremy L. ;

Kaplan, Warren ;

Jones, Marc D. ;

Colvin, Emily K. ;

Nagrial, Adnan M. ;

Humphrey, Emily S. ;

Chou, Angela ;

Chin, Venessa T. ;

Chantrill, Lorraine A. .

NATURE, 2012, 491 (7424) :399-405

[4]

Cell death by mitotic catastrophe: a molecular definition [J].

Castedo, M ;

Perfettini, JL ;

Roumie, T ;

Andreau, K ;

Medema, R ;

Kroemer, G .

ONCOGENE, 2004, 23 (16) :2825-2837

[5]

DNA repair dysregulation from cancer driver to therapeutic target [J].

Curtin, Nicola J. .

NATURE REVIEWS CANCER, 2012, 12 (12) :801-817

[6]

A Functional Cancer Genomics Screen Identifies a Druggable Synthetic Lethal Interaction between MSH3 and PRKDC [J].

Dietlein, Felix ;

Thelen, Lisa ;

Jokic, Mladen ;

Jachimowicz, Ron D. ;

Ivan, Laura ;

Knittel, Gero ;

Leeser, Uschi ;

van Oers, Johanna ;

Edelmann, Winfried ;

Heukamp, Lukas C. ;

Reinhardt, H. Christian .

CANCER DISCOVERY, 2014, 4 (05) :592-605

[7]

Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase [J].

DuPage, Michel ;

Dooley, Alison L. ;

Jacks, Tyler .

NATURE PROTOCOLS, 2009, 4 (07) :1064-1072

[8]

The DNA-damage response in human biology and disease [J].

Jackson, Stephen P. ;

Bartek, Jiri .

NATURE, 2009, 461 (7267) :1071-1078

[9]

A spatially and temporally restricted mouse model of soft tissue sarcoma [J].

Kirsch, David G. ;

Dinulescu, Daniela M. ;

Miller, John B. ;

Grimm, Jan ;

Santiago, Philip M. ;

Young, Nathan P. ;

Nielsen, G. Petur ;

Quade, Bradley J. ;

Chaber, Christopher J. ;

Schultz, Christian P. ;

Takeuchi, Osamu ;

Bronson, Roderick T. ;

Crowley, Denise ;

Korsmeyer, Stanley J. ;

Yoon, Sam S. ;

Hornicek, Francis J. ;

Weissleder, Ralph ;

Jacks, Tyler .

NATURE MEDICINE, 2007, 13 (08) :992-997

[10]

Synergistic drug combinations tend to improve therapeutically relevant selectivity [J].

Lehar, Joseph ;

Krueger, Andrew S. ;

Avery, William ;

Heilbut, Adrian M. ;

Johansen, Lisa M. ;

Price, E. Roydon ;

Rickles, Richard J. ;

Short, Glenn F., III ;

Staunton, Jane E. ;

Jin, Xiaowei ;

Lee, Margaret S. ;

Zimmermann, Grant R. ;

Borisy, Alexis A. .

NATURE BIOTECHNOLOGY, 2009, 27 (07) :659-U116

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