Monday, November 8, 2010

Understanding resistance to targeted cancer therapies via systems biology

On a good day only a small fraction of patients completely respond to modern cancer therapies targeting defined targets, such as EGFR, VEGFR, etc.  The tumors escape, cancer becomes resistant, not only due to accumulation of mutations in the target, but due to reliance on alternate cancer cell survival pathways.  EGFR signaling network is a good example of various pathways cross-talking with each other, creating redundancies and feedback loops.  Robust alternate survival pathways result in poor prognosis for patients.  

 (Fig: Wu C-J et al. PLoS ONE 4(11): e7994.  DOI)

Astsaturov et al. (Science Signaling, September 21st, 2010 issue) took a systems biology approach to identify key redundant and alternate pathways in cancer cells by first identifying >2K genes that constitute the EGFR signaling network.  Of these, using an siRNA approach to systematically downregulate around 600 genes, they narrowed down to 61 genes which were key to tumor escape under anti-EGFR therapy.  

(pic from:

Synthetic Lethal Screen of an EGFR-Centered Network to Improve Targeted Therapies, by Astsaturov et al.
Sci. Signal., 21 September 2010 Vol. 3, Issue 140, p. ra67 | DOI | Scholar |
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. 

Astsaturov et al. have identified NEDD9 as one of the hubs where signals from EGFR/HER2, TGFbeta and Integrins converge.  Disrupting this EGFR/NEDD9/TGF-β interactome is a target (Read WIPO Patent WO/2009/062199 and here ...]  

 (Fig from Prof. Erica A Golemis, PhD, website,

Looking ahead, 13 years from now, I can see companies specializing in creating a cocktail of siRNAs (or small molecules) to partially inhibit these alternate pathways, these cocktails may work as adjuvant, increasing the efficacy of targeted therapies, such as anti-EGFR MAb.  The targeted therapies "will" remain mainstay because by that time, we will have a wealth of clinical experience regarding their toxicity, side-effects, efficacy and, by then, they will be off-patent cheap(!) and more widely accessible/affordable.

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