Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. Signal., 21 September 2010
Vol. 3, Issue 140, p. ra67
[DOI: 10.1126/scisignal.2001083]


Synthetic Lethal Screen of an EGFR-Centered Network to Improve Targeted Therapies

Igor Astsaturov1*, Vladimir Ratushny1,2*, Anna Sukhanova1, Margret B. Einarson1, Tetyana Bagnyukova1, Yan Zhou1, Karthik Devarajan1, Joshua S. Silverman1, Nadezhda Tikhmyanova1,2, Natalya Skobeleva1, Anna Pecherskaya1, Rochelle E. Nasto1,3, Catherine Sharma1, Sandra A. Jablonski4, Ilya G. Serebriiskii1{dagger}, Louis M. Weiner4{dagger}, and Erica A. Golemis1{dagger}

1 Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
2 Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
3 School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, USA.
4 Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057–1468, USA.

* These authors contributed equally to this work.

Abstract: Intrinsic and acquired cellular resistance factors limit the efficacy of most targeted cancer therapeutics. Synthetic lethal screens in lower eukaryotes suggest that networks of genes closely linked to therapeutic targets would be enriched for determinants of drug resistance. We developed a protein network centered on the epidermal growth factor receptor (EGFR), which is a validated cancer therapeutic target, and used small interfering RNA screening to comparatively probe this network for proteins that regulate the effectiveness of both EGFR-targeted agents and nonspecific cytotoxic agents. We identified subnetworks of proteins influencing resistance, with putative resistance determinants enriched among proteins that interacted with proteins at the core of the network. We found that clinically relevant drugs targeting proteins connected in the EGFR network, such as protein kinase C or Aurora kinase A, or the transcriptional regulator signal transducer and activator of transcription 3 (STAT3), synergized with EGFR antagonists to reduce cell viability and tumor size, suggesting the potential for a direct path to clinical exploitation. Such a focused approach can potentially improve the coherent design of combination cancer therapies.

{dagger} To whom correspondence should be addressed. E-mail: weinerl{at} (L.M.W.); ea_golemis{at} (E.A.G.); ig_serebriiskii{at} (I.G.S.)

Citation: I. Astsaturov, V. Ratushny, A. Sukhanova, M. B. Einarson, T. Bagnyukova, Y. Zhou, K. Devarajan, J. S. Silverman, N. Tikhmyanova, N. Skobeleva, A. Pecherskaya, R. E. Nasto, C. Sharma, S. A. Jablonski, I. G. Serebriiskii, L. M. Weiner, E. A. Golemis, Synthetic Lethal Screen of an EGFR-Centered Network to Improve Targeted Therapies. Sci. Signal. 3, ra67 (2010).

Read the Full Text

Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms.
J. Li, K. Bennett, A. Stukalov, B. Fang, G. Zhang, T. Yoshida, I. Okamoto, J.-Y. Kim, L. Song, Y. Bai, et al. (2014)
Mol Syst Biol 9, 705
   Abstract »    Full Text »    PDF »
Molecular Pathways: Sterols and Receptor Signaling in Cancer.
L. Gabitova, A. Gorin, and I. Astsaturov (2014)
Clin. Cancer Res. 20, 28-34
   Abstract »    Full Text »    PDF »
Network Analysis Identifies an HSP90-Central Hub Susceptible in Ovarian Cancer.
H. Liu, F. Xiao, I. G. Serebriiskii, S. W. O'Brien, M. A. Maglaty, I. Astsaturov, S. Litwin, L. P. Martin, D. A. Proia, E. A. Golemis, et al. (2013)
Clin. Cancer Res. 19, 5053-5067
   Abstract »    Full Text »    PDF »
KEAP1-Dependent Synthetic Lethality Induced by AKT and TXNRD1 Inhibitors in Lung Cancer.
B. Dai, S.-Y. Yoo, G. Bartholomeusz, R. A. Graham, M. Majidi, S. Yan, J. Meng, L. Ji, K. Coombes, J. D. Minna, et al. (2013)
Cancer Res. 73, 5532-5543
   Abstract »    Full Text »    PDF »
Inhibiting the HSP90 chaperone slows cyst growth in a mouse model of autosomal dominant polycystic kidney disease.
T. Seeger-Nukpezah, D. A. Proia, B. L. Egleston, A. S. Nikonova, T. Kent, K. Q. Cai, H. H. Hensley, W. Ying, D. Chimmanamada, I. G. Serebriiskii, et al. (2013)
PNAS 110, 12786-12791
   Abstract »    Full Text »    PDF »
Targeting C4-Demethylating Genes in the Cholesterol Pathway Sensitizes Cancer Cells to EGF Receptor Inhibitors via Increased EGF Receptor Degradation.
A. Sukhanova, A. Gorin, I. G. Serebriiskii, L. Gabitova, H. Zheng, D. Restifo, B. L. Egleston, D. Cunningham, T. Bagnyukova, H. Liu, et al. (2013)
Cancer Discovery 3, 96-111
   Abstract »    Full Text »    PDF »
Tankyrase and the Canonical Wnt Pathway Protect Lung Cancer Cells from EGFR Inhibition.
M. Casas-Selves, J. Kim, Z. Zhang, B. A. Helfrich, D. Gao, C. C. Porter, H. A. Scarborough, P. A. Bunn Jr., D. C. Chan, A. C. Tan, et al. (2012)
Cancer Res. 72, 4154-4164
   Abstract »    Full Text »    PDF »
Computational Approaches for Analyzing Information Flow in Biological Networks.
B. Kholodenko, M. B. Yaffe, and W. Kolch (2012)
Science Signaling 5, re1
   Abstract »    Full Text »    PDF »
Delineation of key regulatory elements identifies points of vulnerability in the mitogen-activated signaling network.
N. Jailkhani, S. Ravichandran, S. R. Hegde, Z. Siddiqui, S. C. Mande, and K. V. S. Rao (2011)
Genome Res. 21, 2067-2081
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 4 January 2011.
M. B. Yaffe and A. M. VanHook (2011)
Science Signaling 4, pc1
   Abstract »    Full Text »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882