Targeting LKB1 in cancer - exposing and exploiting vulnerabilities

被引：77

作者：

Momcilovic, M. ^{[1
]}

Shackelford, D. B. ^{[1
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pulm & Crit Care Med, Los Angeles, CA 90095 USA

来源：

BRITISH JOURNAL OF CANCER | 2015年 / 113卷 / 04期

关键词：

LKB1; cancer; therapeutic strategies; vulnerabilities; ACTIVATED PROTEIN-KINASE; CELL LUNG-CANCER; TUBEROUS SCLEROSIS COMPLEX; TUMOR-SUPPRESSOR LKB1; MOUSE MODEL; UPSTREAM KINASE; TYROSINE KINASE; LACTIC-ACIDOSIS; GENE-EXPRESSION; COLON-CANCER;

D O I：

10.1038/bjc.2015.261

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The LKB1 tumour suppressor is a serine/threonine kinase that functions as master regulator of cell growth, metabolism, survival and polarity. LKB1 is frequently mutated in human cancers and research spanning the last two decades have begun decoding the cellular pathways deregulated following LKB1 inactivation. This work has led to the identification of vulnerabilities present in LKB1-deficient tumour cells. Pre-clinical studies have now identified therapeutic strategies targeting this subset of tumours that promise to benefit this large patient population harbouring LKB1 mutations. Here, we review the current efforts that are underway to translate pre-clinical discovery of therapeutic strategies targeting LKB1 mutant cancers into clinical practice.

引用

页码：574 / 584

页数：11

共 134 条

[1] SIK2 Is a Centrosome Kinase Required for Bipolar Mitotic Spindle Formation that Provides a Potential Target for Therapy in Ovarian Cancer [J].

Ahmed, Ahmed Ashour ;

Lu, Zhen ;

Jennings, Nicholas B. ;

Etemadmoghadam, Dariush ;

Capalbo, Luisa ;

Jacamo, Rodrigo O. ;

Barbosa-Morais, Nuno ;

Le, Xiao-Feng ;

Vivas-Mejia, Pablo ;

Lopez-Berestein, Gabriel ;

Grandjean, Geoffrey ;

Bartholomeusz, Geoffrey ;

Liao, Warren ;

Andreeff, Michael ;

Bowtell, David ;

Glover, David M. ;

Sood, Anil K. ;

Bast, Robert C., Jr. .

CANCER CELL, 2010, 18 (02) :109-121

[2] Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia [J].

Alachkar, Houda ;

Mutonga, Martin B. G. ;

Metzeler, Klaus H. ;

Fulton, Noreen ;

Malnassy, Gregory ;

Herold, Tobias ;

Spiekermann, Karsten ;

Bohlander, Stefan K. ;

Hiddemann, Wolfgang ;

Matsuo, Yo ;

Stock, Wendy ;

Nakamura, Yusuke .

ONCOTARGET, 2014, 5 (23) :12371-12382

[3] Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo [J].

Algire, C. ;

Amrein, L. ;

Bazile, M. ;

David, S. ;

Zakikhani, M. ;

Pollak, M. .

ONCOGENE, 2011, 30 (10) :1174-1182

[4] Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss [J].

Andrade-Vieira, Rafaela ;

Goguen, Donna ;

Bentley, Heidi A. ;

Bowen, Chris V. ;

Marignani, Paola A. .

ONCOTARGET, 2014, 5 (24) :12738-12752

[5] Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice [J].

Anisimov, VN ;

Berstein, LM ;

Egormin, PA ;

Piskunova, TS ;

Popovich, IG ;

Zabezhinski, MA ;

Kovalenko, IG ;

Poroshina, TE ;

Semenchenko, AV ;

Provinciali, M ;

Re, F ;

Franceschi, C .

EXPERIMENTAL GERONTOLOGY, 2005, 40 (8-9) :685-693

[6] Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases [J].

Apsel, Beth ;

Blair, Jimmy A. ;

Gonzalez, Beatriz ;

Nazif, Tamim M. ;

Feldman, Morri E. ;

Aizenstein, Brian ;

Hoffman, Randy ;

Williams, Roger L. ;

Shokat, Kevan M. ;

Knight, Zachary A. .

NATURE CHEMICAL BIOLOGY, 2008, 4 (11) :691-699

[7] Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation [J].

Bardeesy, N ;

Sinha, M ;

Hezel, AF ;

Signoretti, S ;

Hathaway, NA ;

Sharpless, NE ;

Loda, M ;

Carrasco, DR ;

DePinho, RA .

NATURE, 2002, 419 (6903) :162-167

[8] 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

[9] Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis [J].

Bissler, John J. ;

McCormack, Francis X. ;

Young, Lisa R. ;

Elwing, Jean M. ;

Chuck, Gail ;

Leonard, Jennifer M. ;

Schmithorst, Vincent J. ;

Laor, Tal ;

Brody, Alan S. ;

Bean, Judy ;

Salisbury, Shelia ;

Franz, David N. .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 358 (02) :140-151

[10] Organoid Models of Human and Mouse Ductal Pancreatic Cancer [J].

Boj, Sylvia F. ;

Hwang, Chang-Il ;

Baker, Lindsey A. ;

Chio, Iok In Christine ;

Engle, Dannielle D. ;

Corbo, Vincenzo ;

Jager, Myrthe ;

Ponz-Sarvise, Mariano ;

Tiriac, Herve ;

Spector, Mona S. ;

Gracanin, Ana ;

Oni, Tobiloba ;

Yu, Kenneth H. ;

van Boxtel, Ruben ;

Huch, Meritxell ;

Rivera, Keith D. ;

Wilson, John P. ;

Feigin, Michael E. ;

Oehlund, Daniel ;

Handly-Santana, Abram ;

Ardito-Abraham, Christine M. ;

Ludwig, Michael ;

Elyada, Ela ;

Alagesan, Brinda ;

Biffi, Giulia ;

Yordanov, Georgi N. ;

Delcuze, Bethany ;

Creighton, Brianna ;

Wright, Kevin ;

Park, Youngkyu ;

Morsink, Folkert H. M. ;

Molenaar, I. Quintus ;

Rinkes, Inne H. Borel ;

Cuppen, Edwin ;

Hao, Yuan ;

Jin, Ying ;

Nijman, Isaac J. ;

Iacobuzio-Donahue, Christine ;

Leach, Steven D. ;

Pappin, Darryl J. ;

Hammell, Molly ;

Klimstra, David S. ;

Basturk, Olca ;

Hruban, Ralph H. ;

Offerhaus, George Johan ;

Vries, Robert G. J. ;

Clevers, Hans ;

Tuveson, David A. .

CELL, 2015, 160 (1-2) :324-338

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