Can systems biology understand pathway activation? Gene expression signatures as surrogate markers for understanding the complexity of pathway activation

Abstract

Cancer is thought to be caused by a sequence of multiple genetic and epigenetic alterations which occur in one or more of the genes controlling cell cycle progression and signaling transduction. The complexity of carcinogenic mechanisms leads to heterogeneity in molecular phenotype, pathology, and prognosis of cancers.Genome-wide mutational analysis of cancer genes in individual tumors is the most direct way to elucidate the complex process of disease progression, although such high-throughput sequencing technologies are not yet fully developed. As a surrogate marker for pathway activation analysis, expression profiling using microarrays has been successfully applied for the classification of tumor types, stages of tumor progression, or in some cases, prediction of clinical outcomes. However, the biological implication of those gene expression signatures is often unclear. Systems biological approaches leverage the signature genes as a representation of changes in signaling pathways, instead of interpreting the relevance between each gene and phenotype. This approach, which can be achieved by comparing the gene set or the expression profile with those of reference experiments in which a defined pathway is modulated, will improve our understanding of cancer classification, clinical outcome, and carcinogenesis. In this review, we will discuss recent studies on the development of expression signatures to monitor signaling pathway activities and how these signatures can be used to improve the identification of responders to anticancer drugs.

Keywords: Expression signature; cancer therapy; drug discovery; signaling pathway; systems biology..

Fig. (1)

Methods to develop pathway signatures. Gene expression regulated by signaling pathways can be detected by comparing pathway-activated vs. quiescent cells or baseline-level vs. inactivated cells using gene expression microarrays (See text for detail).

Fig. (2)

Expected application of pathway signatures to personalized medicine. In many diseases including cancer, the disorder is caused by deregulation of cellular signaling. Pathway signatures can be a novel tool to assess signaling statuses. The pathway activation/inactivation status in each patient will be monitored by the expression profile and a set of pathway signatures. Identification of the causative pathway allows us to select the "right" drug to inhibit the pathway.

Fig. (3)

Response to pathway inhibitors of tumor cells depends on the mechanism of pathway activation. (a) Tumor cells with EGFR mutation are sensitive to EGFR inhibitor gefitinib or erlotinib, whereas those with RAS mutation are resistant to the same drug, because RAF-MEK-ERK signaling is not inhibited by the drugs. (b) When the PI3K pathway is hyperactivated by PI3K mutation or by PTEN loss, tumor cells are sensitive to rapamycin, which inhibits mTOR downstream of the pathway. However, the HER2 inhibitor Herceptin cannot stop the deregulated signal, because it does not inhibit hyperactivation downstream.