Metabolic and Functional Genomic Studies Identify Deoxythymidylate Kinase as a Target in LKB1-Mutant Lung Cancer

被引：116

作者：

Liu, Yan ^{[1
,4
,5
,6
]}

Marks, Kevin ^{[9
]}

Cowley, Glenn S. ^{[10
]}

Carretero, Julian ^{[16
]}

Liu, Qingsong ^{[2
]}

Nieland, Thomas J. F. ^{[10
]}

Xu, Chunxiao ^{[1
,4
,5
,6
]}

Cohoon, Travis J. ^{[1
,4
,5
,6
]}

Gao, Peng ^{[1
,4
,5
,6
]}

Zhang, Yong ^{[1
,4
]}

Chen, Zhao ^{[1
,4
,5
,6
]}

Altabef, Abigail B. ^{[1
,4
,5
,6
]}

Tchaicha, Jeremy H. ^{[1
,4
,5
,6
]}

Wang, Xiaoxu ^{[1
,3
]}

Choe, Sung ^{[9
]}

Driggers, Edward M. ^{[9
]}

Zhang, Jianming ^{[2
]}

Bailey, Sean T. ^{[11
,12
]}

Sharpless, Norman E. ^{[11
,12
]}

Hayes, D. Neil ^{[11
,12
]}

Patel, Nirali M. ^{[11
,12
]}

Janne, Pasi A. ^{[1
,4
,5
]}

Bardeesy, Nabeel ^{[1
,7
]}

Engelman, Jeffrey A. ^{[1
,7
]}

Manning, Brendan D. ^{[8
]}

Shaw, Reuben J. ^{[13
]}

Asara, John M.

Scully, Ralph ^{[13
]}

Kimmelman, Alec ^{[1
,3
]}

Byers, Lauren A. ^{[14
]}

Gibbons, Don L. ^{[14
]}

Wistuba, Ignacio I. ^{[14
]}

Heymach, John V. ^{[14
]}

Kwiatkowski, David J. ^{[1
,4
,5
]}

Kim, William Y. ^{[11
,12
]}

Kung, Andrew L. ^{[15
]}

Gray, Nathanael S. ^{[2
]}

Root, David E. ^{[10
]}

Cantley, Lewis C. ^{[1
]}

Wong, Kwok-Kin ^{[1
,4
,5
,6
]}

机构：

[1] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA

[2] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA

[3] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Radiat Oncol, Boston, MA 02215 USA

[4] Harvard Univ, Sch Publ Hlth, Dept Med Oncol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Publ Hlth, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA

[6] Harvard Univ, Sch Publ Hlth, Ludwig Ctr, Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA

[7] Harvard Univ, Sch Publ Hlth, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02115 USA

[8] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA

[9] Agios Pharmaceut, Cambridge, MA USA

[10] Broad Inst MIT & Harvard, Cambridge, MA USA

[11] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[12] Univ N Carolina, Dept Med & Genet, Chapel Hill, NC 27599 USA

[13] Salk Inst Biol Studies, Mol & Cell Biol Lab, La Jolla, CA 92037 USA

[14] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[15] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10027 USA

[16] Univ Valencia, Dept Physiol, E-46100 Burjassot, Spain

来源：

CANCER DISCOVERY | 2013年 / 3卷 / 08期

关键词：

DNA-DAMAGE; THYMIDYLATE KINASE; THYMINELESS DEATH; MASS-SPECTROMETRY; CELL POLARITY; LKB1; PATHWAY; GROWTH; IDENTIFICATION; INACTIVATION;

D O I：

10.1158/2159-8290.CD-13-0015

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase, which coordinates cell growth, polarity, motility, and metabolism. In non-small cell lung carcinoma, LKB1 is somatically inactivated in 25% to 30% of cases, often concurrently with activating KRAS mutations. Here, we used an integrative approach to define novel therapeutic targets in KRAS-driven LKB1-mutant lung cancers. High-throughput RNA interference screens in lung cancer cell lines from genetically engineered mouse models driven by activated KRAS with or without coincident Lkb1 deletion led to the identification of Dtymk, encoding deoxythymidylate kinase (DTYMK), which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 deficiency in mouse and human lung cancer lines. Global metabolite profiling showed that Lkb1-null cells had a striking decrease in multiple nucleotide metabolites as compared with the Lkb1-wild-type cells. Thus, LKB1-mutant lung cancers have deficits in nucleotide metabolism that confer hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors. (C) 2013 AACR.

引用

页码：870 / 879

页数：10

共 36 条

[1] Thymine metabolism and thymineless death in prokaryotes and eukaryotes [J].

Ahmad, SI ;

Kirk, SH ;

Eisenstark, A .

ANNUAL REVIEW OF MICROBIOLOGY, 1998, 52 :591-625

[2] MAMMALIAN DEOXYRIBONUCLEOSIDE KINASES [J].

ARNER, ESJ ;

ERIKSSON, S .

PHARMACOLOGY & THERAPEUTICS, 1995, 67 (02) :155-186

[3] RIBONUCLEOTIDE REDUCTASE - REGULATION, REGULATION, REGULATION [J].

ELLEDGE, SJ ;

ZHENG, Z ;

ALLEN, JB .

TRENDS IN BIOCHEMICAL SCIENCES, 1992, 17 (03) :119-123

[4] Pathways of Resistance to Thymineless Death in Escherichia coli and the Function of UvrD [J].

Fonville, Natalie C. ;

Vaksman, Zalman ;

DeNapoli, Jessica ;

Hastings, P. J. ;

Rosenberg, Susan M. .

GENETICS, 2011, 189 (01) :23-U611

[5] How nucleotide excision repair protects against cancer [J].

Friedberg, EC .

NATURE REVIEWS CANCER, 2001, 1 (01) :22-33

[6] High-Throughput, Accurate Mass Metabolome Profiling of Cellular Extracts by Flow Injection - Time-of-Flight Mass Spectrometry [J].

Fuhrer, Tobias ;

Heer, Dominik ;

Begemann, Boris ;

Zamboni, Nicola .

ANALYTICAL CHEMISTRY, 2011, 83 (18) :7074-7080

[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] The Lkb1 metabolic sensor maintains haematopoietic stem cell survival [J].

Gurumurthy, Sushma ;

Xie, Stephanie Z. ;

Alagesan, Brinda ;

Kim, Judith ;

Yusuf, Rushdia Z. ;

Saez, Borja ;

Tzatsos, Alexandros ;

Ozsolak, Fatih ;

Milos, Patrice ;

Ferrari, Francesco ;

Park, Peter J. ;

Shirihai, Orian S. ;

Scadden, David T. ;

Bardeesy, Nabeel .

NATURE, 2010, 468 (7324) :659-U75

[9] Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation [J].

Heiden, Matthew G. Vander ;

Cantley, Lewis C. ;

Thompson, Craig B. .

SCIENCE, 2009, 324 (5930) :1029-1033

[10] Synthetic lethality by lentiviral short hairpin RNA silencing of thymidylate kinase and doxorubicin in colon cancer cells regardless of the p53 status [J].

Hu, Chun-Mei ;

Chang, Zee-Fen .

CANCER RESEARCH, 2008, 68 (08) :2831-2840

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