Towards pathway‐centric cancer therapies via pharmacogenomic profiling analysis of ERK signalling pathway

Abstract

Background: Genomic heterogeneity in human cancers complicates gene-centric personalized medicine. Malignant tumors often share a core group of pathways that are perturbed by diverse genetic mutations. Therefore, one possible solution to overcome the heterogeneity challenge is a shift from gene-centric to pathway-centric therapies. Pathway-centric perspectives, which underscore the need to understand key pathways and their critical properties, could address the complexity of cancer heterogeneity better than gene-centric approaches to aid cancer drug discovery and therapy. Methods: We used large-scale pharmacogenomic profiling data provided by the Cancer Genome Project of the Well-come Trust Sanger Institute and the Cancer Cell Line Encyclopedia. In a systematic in silico investigation of ERK signal-ling pathway components and topological structures determines their influences on pathway activity and targeted therapies. Mann–Whitney U test was used to identify gene alterations associated with drug sensitivity with p values and Benjamini–Hochberg correction for multiple hypotheses testing. Results: The analysis demonstrated that genetic alterations were crucial to activation of effector pathway and sub-sequent tumorigenesis, however drug sensitivity suffered from both drug effector and non-effector pathways, which were determined by not only underlying genomic alterations, but also interplay and topological relationship of com-ponents in pathway, suggesting that the combinatorial targets of key nodes in perturbed pathways may yield better treatment outcome. Furthermore, we proposed a model to provide a more comprehensive insight and understand-ing of pathway-centric cancer therapies. Conclusions: Our study provides a holistic view of factors influencing drug sensitivity and sheds light on pathway-centric cancer therapies.