Inhibiting Tankyrases Sensitizes KRAS-Mutant Cancer Cells to MEK Inhibitors via FGFR2 Feedback Signaling

被引:33
作者
Schoumacher, Marie [1 ]
Hurov, Kristen E. [1 ]
Lehar, Joseph [1 ]
Yan-Neale, Yan [1 ]
Mishina, Yuji [1 ]
Sonkin, Dmitriy [1 ]
Korn, Joshua M. [1 ]
Flemming, Daisy [1 ]
Jones, Michael D. [1 ]
Antonakos, Brandon [1 ]
Cooke, Vesselina G. [1 ]
Steiger, Janine [2 ]
Ledell, Jebediah [2 ]
Stump, Mark D. [1 ]
Sellers, William R. [1 ]
Danial, Nika N. [3 ]
Shao, Wenlin [1 ]
机构
[1] Novartis Inst BioMed Res, Dept Oncol, Cambridge, MA 02139 USA
[2] Zalicus Inc, Cambridge, MA USA
[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA
关键词
WNT PATHWAY; ADP-RIBOSYLATION; ACTIVATION; MOLECULE; PI3K; RESISTANCE; POLY(ADP-RIBOSE); THERAPEUTICS; CHERUBISM; THERAPY;
D O I
10.1158/0008-5472.CAN-14-0138-T
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis, and mitosis, offering attractive targets for anticancer treatment. Using unbiased combination screening in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors (MEKi) in KRAS-mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and antitumor activity both in vitro and in vivo than effects observed by previously reported MEKi combinations. Altogether, our results show how a novel combination of TNKS and MEK inhibitors can be highly effective in targeting KRAS-mutant cancers by suppressing a newly discovered resistance mechanism. (C) 2014 AACR.
引用
收藏
页码:3294 / 3305
页数:12
相关论文
共 43 条
[1]   The PARP superfamily [J].
Amé, JC ;
Spenlehauer, C ;
de Murcia, G .
BIOESSAYS, 2004, 26 (08) :882-893
[2]   Inhibition of Tankyrases Induces Axin Stabilization and Blocks Wnt Signalling in Breast Cancer Cells [J].
Bao, Renyue ;
Christova, Tania ;
Song, Siyuan ;
Angers, Stephane ;
Yan, Xiaojun ;
Attisano, Liliana .
PLOS ONE, 2012, 7 (11)
[3]   Mining the Wnt pathway for cancer therapeutics [J].
Barker, Nick ;
Clevers, Hans .
NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (12) :997-1014
[4]   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
[5]   Wnt/β-Catenin Signaling and AXIN1 Regulate Apoptosis Triggered by Inhibition of the Mutant Kinase BRAFV600E in Human Melanoma [J].
Biechele, Travis L. ;
Kulikauskas, Rima M. ;
Toroni, Rachel A. ;
Lucero, Olivia M. ;
Swift, Reyna D. ;
James, Richard G. ;
Robin, Nick C. ;
Dawson, David W. ;
Moon, Randall T. ;
Chien, Andy J. .
SCIENCE SIGNALING, 2012, 5 (206)
[6]   Discovery of a Class of Novel Tankyrase Inhibitors that Bind to Both the Nicotinamide Pocket and the Induced Pocket [J].
Bregman, Howard ;
Gunaydin, Hakan ;
Gu, Yan ;
Schneider, Steve ;
Wilson, Cindy ;
DiMauro, Erin F. ;
Huang, Xin .
JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (03) :1341-1345
[7]   Tankyrase and the Canonical Wnt Pathway Protect Lung Cancer Cells from EGFR Inhibition [J].
Casas-Selves, Matias ;
Kim, Jihye ;
Zhang, Zhiyong ;
Helfrich, Barbara A. ;
Gao, Dexiang ;
Porter, Christopher C. ;
Scarborough, Hannah A. ;
Bunn, Paul A., Jr. ;
Chan, Daniel C. ;
Tan, Aik Choon ;
DeGregori, James .
CANCER RESEARCH, 2012, 72 (16) :4154-4164
[8]   AKT Inhibition Relieves Feedback Suppression of Receptor Tyrosine Kinase Expression and Activity [J].
Chandarlapaty, Sarat ;
Sawai, Ayana ;
Scaltriti, Maurizio ;
Rodrik-Outmezguine, Vanessa ;
Grbovic-Huezo, Olivera ;
Serra, Violeta ;
Majumder, Pradip K. ;
Baselga, Jose ;
Rosen, Neal .
CANCER CELL, 2011, 19 (01) :58-71
[9]   Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer [J].
Chen, Baozhi ;
Dodge, Michael E. ;
Tang, Wei ;
Lu, Jianming ;
Ma, Zhiqiang ;
Fan, Chih-Wei ;
Wei, Shuguang ;
Hao, Wayne ;
Kilgore, Jessica ;
Williams, Noelle S. ;
Roth, Michael G. ;
Amatruda, James F. ;
Chen, Chuo ;
Lum, Lawrence .
NATURE CHEMICAL BIOLOGY, 2009, 5 (02) :100-107
[10]   Proteasome Regulation by ADP-Ribosylation [J].
Cho-Park, Park F. ;
Steller, Hermann .
CELL, 2013, 153 (03) :614-627