Drug Resistance Mechanisms in Colorectal Cancer Dissected with Cell Type–Specific Dynamic Logic Models

Abstract

Genomic features are used as biomarkers of sensitivity to kinase inhibitors used widely to treat human cancer, but effective patient stratification based on these principles remains limited in impact. Insofar as kinase inhibitors interfere with signaling dynamics, and, in turn, signaling dynamics affects inhibitor responses, we investigated associations in this study between cell-specific dynamic signaling pathways and drug sensitivity. Specifically, we measured 14 phosphoproteins under 43 different perturbed conditions (combinations of 5 stimuli and 7 inhibitors) in 14 colorectal cancer cell lines, building cell line-specific dynamic logic models of underlying signaling networks. Model parameters representing pathway dynamics were used as features to predict sensitivity to a panel of 27 drugs. Specific parameters of signaling dynamics correlated strongly with drug sensitivity for 14 of the drugs, 9 of which had no genomic biomarker. Following one of these associations, we validated a drug combination predicted to overcome resistance to MEK inhibitors by co-blockade of GSK3, which was not found based on associations with genomic data. These results suggest that, in order to better understand cancer resistance and move toward personalized medicine, it is essential to consider signaling network dynamics that can not be inferred from static genotypes.

A cancer pharmacogenomic screen powering crowd-sourced advancement of drug combination prediction

“…A notable absence from the Challenge was the use of mathematical, boolean or logic based mechanistic pathway modelling approaches [25][26][27][28][29] , likely due to the intensity of model creation. The dynamic nature of mechanistic models may offer an advantage by enabling consideration of the heterogeneity that exists across even apparently 'clonal' cell line populations 21 .…”

Opposing effects of low versus high concentrations of water soluble vitamins/dietary ingredients Vitamin C and niacin on colon cancer stem cells (CSCs)

“…Less than 1% population amongst the colorectal cancer niche also known as the cancer stem cells (CSCs) or tumourinitiating cells (TICs) are the rogue population of cells that are responsible for cancer relapse (Bagheri et al 2017). Hence, 90% of the drug failures in metastatic cancer are due to chemoresistance (Longley and Johnston, 2005;Eduati et al 2017). Moreover, the CSCs have the capacity to regenerate the bulk of cancer.…”

A Flexible Approach for Context‐Dependent Assessment of Quantitative Systems Pharmacology Models

“…Although context influences how and to what extent each major assessment area is addressed, all areas should be considered and discussed. Figure shows how contextual considerations can influence the degree of rigor required in model assessment and indicates the different context surrounding example models of cancer signaling pathways . Here, we discuss how context influences model assessment for two of these studies …”