Oncogene. 2013 Aug 15;32(33):3809-18. doi: 10.1038/onc.2012.389.

Gene signature critical to cancer phenotype as a paradigm for anticancer drug discovery.

Sampson ER, McMurray HR, Hassane DC, Newman L, Salzman P, Jordan CT, Land H.

Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.

 

Abstract

Malignant cell transformation commonly results in the deregulation of thousands of cellular genes, an observation that suggests a complex biological process and an inherently challenging scenario for the development of effective cancer interventions. To better define the genes/pathways essential to regulating the malignant phenotype, we recently described a novel strategy based on the cooperative nature of carcinogenesis that focuses on genes synergistically deregulated in response to cooperating oncogenic mutations. These so-called ‘cooperation response genes’ (CRGs) are highly enriched for genes critical for the cancer phenotype, thereby suggesting their causal role in the malignant state. Here, we show that CRGs have an essential role in drug-mediated anticancer activity and that anticancer agents can be identified through their ability to antagonize the CRG expression profile. These findings provide proof-of-concept for the use of the CRG signature as a novel means of drug discovery with relevance to underlying anticancer drug mechanisms.

PMID: 22964631

 

SUPPLEMENT: 

Here we provide proof-of-concept that a gene expression signature comprising genes essential to the cancer phenotype has utility for discovery of anti-cancer agents and their underlying mechanisms of action. Previously we have shown that drivers of the cancer phenotype downstream of oncogenic mutations can be identified based on their synergistic deregulation by cooperating oncogenic mutations. We now demonstrate that these so-called “cooperation response genes” (CRGs) play an essential role in drug-mediated anti-cancer activity and that anti-cancer agents can be identified through their ability to reverse the CRG expression profile. Notably, reversal of CRG expression by anti-cancer agents appears integral to underlying drug mechanism. Our data thus reveal the CRG expression profile as a powerful probe to identify anti-cancer agents acting downstream of multiple cancer gene mutations.

Specifically, we show that the CRG signature is antagonized by histone deacetylase inhibitors (HDI) in a cancer cell-specific manner, and that such reversal of CRG expression is essential for HDI anti-cancer activity. Among the HDI-regulated CRGs are a number of genes that are repressed in transformed cells and reactivated by HDI. These include Dapk1, Fas, Notch3, Noxa and Perp. We thus demonstrate that reversal of CRG expression by pharmacological agents is integral to the underlying anti-cancer drug mechanism and that the mechanism involved may be multi-dimensional in nature.

Our observation that reversion of the CRG signature is essential for the tumor inhibitory activity of anti-cancer compounds has important practical implications. First, the CRG signature provides a new means for anti-cancer drug discovery based on insights relating to drug mechanism. CRG expression patterns thus may serve as an indicator for anti-tumor activity, as a surrogate for tumor cell behavior in vivo, thereby facilitating identification of potential anti-cancer compounds, perhaps with relevance to multiple types of human cancer. Second, we envisage that the responsiveness of the CRG signature to pharmacologic agents can also function as a diagnostic indicator of cancer cell sensitivity to such agents, wherever CRGs contribute to the cancer phenotype.

Land Hartmut-fig1

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