Kinase requirements in human cells: III. Altered kinase requirements in VHL-/- cancer cells detected in a pilot synthetic lethal screen

被引：119

作者：

Bommi-Reddy, Archana ^{[2
]}

Almeciga, Ingrid ^{[2
]}

Sawyer, Jacqueline ^{[1
]}

Geisen, Christoph ^{[2
,3
]}

Li, Wenliang ^{[1
]}

Harlow, Ed ^{[1
]}

Kaelin, William G., Jr. ^{[2
,3
]}

Grueneberg, Dorre A. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2008年 / 105卷 / 43期

基金：

美国国家卫生研究院;

关键词：

essential kinases; shRNA screens; VHL; kidney cancer; therapeutics;

D O I：

10.1073/pnas.0806574105

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 [理学]; 0710 [生物学]; 09 [农学];

摘要：

Clear cell renal carcinomas are the most common form of kidney cancer and frequently are linked to biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. The VHL gene product, pVHL, has multiple functions including directing the polyubiquitylation of the HIF transcription factor. We screened 100 shRNA vectors, directed against 88 kinases, for their ability to inhibit the viability of VHL-/- renal carcinoma cells preferentially compared with isogenic cells in which pVHL function was restored. shRNAs for "hits" identified in the primary screen were interrogated in secondary screens that included shRNA titration studies. Multiple shRNAs against CDK6, MET, and MAP2K1 (also known as MEK1) preferentially inhibited the viability of 786-O and RCC4 VHL-/- cells compared with their wild-type pVHL-reconstituted counterparts. The sensitivity of pVHL-proficient cells to these shRNAs was not restored upon HIF activation, suggesting that loss of an hypoxia-inducible factor (HIF)-independent pVHL function formed the basis for selectivity. A small-molecule Cdk4/6 inhibitor displayed enhanced activity against VHL-/- renal carcinoma cells, suggesting that in some cases hits from shRNA screens such as described here might translate into therapeutic targets.

引用

页码：16484 / 16489

页数：6

共 35 条

[1]

A large-scale RNAi screen in human cells identifies new components of the p53 pathway [J].

Berns, K ;

Hijmans, EM ;

Mullenders, J ;

Brummelkamp, TR ;

Velds, A ;

Heimerikx, M ;

Kerkhoven, RM ;

Madiredjo, M ;

Nijkamp, W ;

Weigelt, B ;

Agami, R ;

Ge, W ;

Cavet, G ;

Linsley, PS ;

Beijersbergen, RL ;

Bernards, R .

NATURE, 2004, 428 (6981) :431-437

[2]

Bindra RS, 2002, CANCER RES, V62, P3014

[3]

Role of transforming growth factor-α in von Hippel-Lindau (VHL)-/- clear cell renal carcinoma cell proliferation:: A possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis [J].

de Paulsen, N ;

Brychzy, A ;

Fournier, MC ;

Klausner, RD ;

Gnarra, JR ;

Pause, A ;

Lee, S .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (04) :1387-1392

[4]

Kinase requirements in human cells: I. Comparing kinase requirements across various cell types [J].

Grueneberg, Dorre A. ;

Degott, Sebastien ;

Pearlberg, Joseph ;

Li, Wenliang ;

Davies, Joan E. ;

Baldwin, Amy ;

Endege, Wilson ;

Doench, John ;

Sawyer, Jacqueline ;

Hu, Yanhui ;

Boyce, Frederick ;

Xian, Jun ;

Munger, Karl ;

Harlow, Ed .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (43) :16472-16477

[5]

Integrating genetic approaches into the discovery of anticancer drugs [J].

Hartwell, LH ;

Szankasi, P ;

Roberts, CJ ;

Murray, AW ;

Friend, SH .

SCIENCE, 1997, 278 (5340) :1064-1068

[6]

Mitogen-activated protein kinase kinase inhibitor PD98059 blocks the trans-activation but not the stabilization or DNA binding ability of hypoxia-inducible factor-1α [J].

Hur, E ;

Chang, KY ;

Lee, E ;

Lee, SK ;

Park, H .

MOLECULAR PHARMACOLOGY, 2001, 59 (05) :1216-1224

[7]

TUMOR SUPPRESSION BY THE HUMAN VON HIPPEL-LINDAU GENE-PRODUCT [J].

ILIOPOULOS, O ;

KIBEL, A ;

GRAY, S ;

KAELIN, WG .

NATURE MEDICINE, 1995, 1 (08) :822-826

[8]

Cell biology - Divining cancer cell weaknesses [J].

Kaelin, WG .

NATURE, 2006, 441 (7089) :32-34

[9]

The concept of synthetic lethality in the context of anticancer therapy [J].

Kaelin, WG .

NATURE REVIEWS CANCER, 2005, 5 (09) :689-698

[10]

von Hippel-Lindau disease [J].

Kaelin, William G., Jr. .

ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE, 2007, 2 :145-173

← 1 2 3 4 →