Synthetic Lethal Interaction of Combined BCL-XL and MEK Inhibition Promotes Tumor Regressions in KRAS Mutant Cancer Models

被引：321

作者：

Corcoran, Ryan B. ^{[1
,2
]}

Cheng, Katherine A. ^{[3
]}

Hata, Aaron N. ^{[1
,2
]}

Faber, Anthony C. ^{[1
,2
]}

Ebi, Hiromichi ^{[1
,2
]}

Coffee, Erin M. ^{[1
,4
]}

Greninger, Patricia ^{[1
]}

Brown, Ronald D. ^{[1
]}

Godfrey, Jason T. ^{[1
]}

Cohoon, Travis J. ^{[3
]}

Song, Youngchul ^{[1
]}

Lifshits, Eugene ^{[1
]}

Hung, Kenneth E. ^{[4
]}

Shioda, Toshi ^{[1
]}

Dias-Santagata, Dora ^{[5
]}

Singh, Anurag ^{[6
]}

Settleman, Jeffrey ^{[7
]}

Benes, Cyril H. ^{[1
]}

Mino-Kenudson, Mari ^{[5
]}

Wong, Kwok-Kin ^{[3
]}

Engelman, Jeffrey A. ^{[1
,2
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA

[2] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Boston, MA 02114 USA

[4] Tufts Med Ctr, Div Gastroenterol, Boston, MA 02111 USA

[5] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA

[6] Boston Univ, Boston, MA 02118 USA

[7] Genentech Inc, San Francisco, CA 94080 USA

来源：

CANCER CELL | 2013年 / 23卷 / 01期

关键词：

GENE-EXPRESSION SIGNATURE; RAS ONCOGENE; K-RAS; APOPTOSIS; CELLS; SENSITIVITY; ACTIVATION; RESISTANCE; INDUCTION; PATHWAYS;

D O I：

10.1016/j.ccr.2012.11.007

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

KRAS is the most commonly mutated oncogene, yet no effective targeted therapies exist for KRAS mutant cancers. We developed a pooled shRNA-drug screen strategy to identify genes that, when inhibited, cooperate with MEK inhibitors to effectively treat KRAS mutant cancer cells. The anti-apoptotic BH3 family gene BCL-XL emerged as a top hit through this approach. ABT-263 (navitoclax), a chemical inhibitor that blocks the ability of BCL-XL to bind and inhibit pro-apoptotic proteins, in combination with a MEK inhibitor led to dramatic apoptosis in many KRAS mutant cell lines from different tissue types. This combination caused marked in vivo tumor regressions in KRAS mutant xenografts and in a genetically engineered KRAS-driven lung cancer mouse model, supporting combined BCL-XL/MEK inhibition as a potential therapeutic approach for KRAS mutant cancers.

引用

页码：121 / 128

页数：8

共 28 条

[1] Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers [J].

Adjei, Alex A. ;

Cohen, Roger B. ;

Franklin, Wilbur ;

Morris, Clive ;

Wilson, David ;

Molina, Julian R. ;

Hanson, Lorelei J. ;

Gore, Lia ;

Chow, Laura ;

Leong, Stephen ;

Maloney, Lara ;

Gordon, Gilad ;

Simmons, Heidi ;

Marlow, Allison ;

Litwiler, Kevin ;

Brown, Suzy ;

Poch, Gregory ;

Kane, Katie ;

Haney, Jerry ;

Eckhardt, S. Gail .

JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (13) :2139-2146

[2]

[Anonymous], J CLIN ONCOL S

[3] Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 [J].

Barbie, David A. ;

Tamayo, Pablo ;

Boehm, Jesse S. ;

Kim, So Young ;

Moody, Susan E. ;

Dunn, Ian F. ;

Schinzel, Anna C. ;

Sandy, Peter ;

Meylan, Etienne ;

Scholl, Claudia ;

Froehling, Stefan ;

Chan, Edmond M. ;

Sos, Martin L. ;

Michel, Kathrin ;

Mermel, Craig ;

Silver, Serena J. ;

Weir, Barbara A. ;

Reiling, Jan H. ;

Sheng, Qing ;

Gupta, Piyush B. ;

Wadlow, Raymond C. ;

Le, Hanh ;

Hoersch, Sebastian ;

Wittner, Ben S. ;

Ramaswamy, Sridhar ;

Livingston, David M. ;

Sabatini, David M. ;

Meyerson, Matthew ;

Thomas, Roman K. ;

Lander, Eric S. ;

Mesirov, Jill P. ;

Root, David E. ;

Gilliland, D. Gary ;

Jacks, Tyler ;

Hahn, William C. .

NATURE, 2009, 462 (7269) :108-U122

[4] Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic [J].

Cragg, Mark S. ;

Jansen, Elisa S. ;

Cook, Michele ;

Harris, Claire ;

Strasser, Andreas ;

Scott, Clare L. .

JOURNAL OF CLINICAL INVESTIGATION, 2008, 118 (11) :3651-3659

[5] Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers [J].

Engelman, Jeffrey A. ;

Chen, Liang ;

Tan, Xiaohong ;

Crosby, Katherine ;

Guimaraes, Alexander R. ;

Upadhyay, Rabi ;

Maira, Michel ;

McNamara, Kate ;

Perera, Samanthi A. ;

Song, Youngchul ;

Chirieac, Lucian R. ;

Kaur, Ramneet ;

Lightbown, Angela ;

Simendinger, Jessica ;

Li, Timothy ;

Padera, Robert F. ;

Garcia-Echeverria, Carlos ;

Weissleder, Ralph ;

Mahmood, Umar ;

Cantley, Lewis C. ;

Wong, Kwok-Kin .

NATURE MEDICINE, 2008, 14 (12) :1351-1356

[6] Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition [J].

Faber, Anthony C. ;

Li, Danan ;

Song, YoungChul ;

Liang, Mei-Chih ;

Yeap, Beow Y. ;

Bronson, Roderick T. ;

Lifshits, Eugene ;

Chen, Zhao ;

Maira, Sauveur-Michel ;

Garcia-Echeverria, Carlos ;

Wong, Kwok-Kin ;

Engelman, Jeffrey A. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (46) :19503-19508

[7] Systematic identification of genomic markers of drug sensitivity in cancer cells [J].

Garnett, Mathew J. ;

Edelman, Elena J. ;

Heidorn, Sonja J. ;

Greenman, Chris D. ;

Dastur, Anahita ;

Lau, King Wai ;

Greninger, Patricia ;

Thompson, I. Richard ;

Luo, Xi ;

Soares, Jorge ;

Liu, Qingsong ;

Iorio, Francesco ;

Surdez, Didier ;

Chen, Li ;

Milano, Randy J. ;

Bignell, Graham R. ;

Tam, Ah T. ;

Davies, Helen ;

Stevenson, Jesse A. ;

Barthorpe, Syd ;

Lutz, Stephen R. ;

Kogera, Fiona ;

Lawrence, Karl ;

McLaren-Douglas, Anne ;

Mitropoulos, Xeni ;

Mironenko, Tatiana ;

Thi, Helen ;

Richardson, Laura ;

Zhou, Wenjun ;

Jewitt, Frances ;

Zhang, Tinghu ;

O'Brien, Patrick ;

Boisvert, Jessica L. ;

Price, Stacey ;

Hur, Wooyoung ;

Yang, Wanjuan ;

Deng, Xianming ;

Butler, Adam ;

Choi, Hwan Geun ;

Chang, JaeWon ;

Baselga, Jose ;

Stamenkovic, Ivan ;

Engelman, Jeffrey A. ;

Sharma, Sreenath V. ;

Delattre, Olivier ;

Saez-Rodriguez, Julio ;

Gray, Nathanael S. ;

Settleman, Jeffrey ;

Futreal, P. Andrew ;

Haber, Daniel A. .

NATURE, 2012, 483 (7391) :570-U87

[8]

Infante JR., 2010, J CLIN ONCOL, V28, p15s

[9] Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras [J].

Jackson, EL ;

Willis, N ;

Mercer, K ;

Bronson, RT ;

Crowley, D ;

Montoya, R ;

Jacks, T ;

Tuveson, DA .

GENES & DEVELOPMENT, 2001, 15 (24) :3243-3248

[10] Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia [J].

Konopleva, Marina ;

Contractor, Rooha ;

Tsao, Twee ;

Samudio, Ismael ;

Ruvalo, Peter P. ;

Kitada, Shinichi ;

Deng, Xingming ;

Zhai, Dayong ;

Shi, Yue-Xi ;

Sneed, Thomas ;

Verhaegen, Monique ;

Soengas, Maria ;

Ruvolo, Vivian R. ;

McQueen, Teresa ;

Schober, Wendy D. ;

Watt, Julie C. ;

Jiffar, Tilahun ;

Ling, Xiaoyang ;

Marini, Frank C. ;

Harris, David ;

Dietrich, Martin ;

Estrov, Zeev ;

McCubrey, James ;

May, W. Stratford ;

Reed, John C. ;

Andreeff, Michael .

CANCER CELL, 2006, 10 (05) :375-388

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