A Test of Highly Optimized Tolerance Reveals Fragile Cell-Cycle Mechanisms Are Molecular Targets in Clinical Cancer Trials

Abstract

Robustness, a long-recognized property of living systems, allows function in the face of uncertainty while fragility, i.e., extreme sensitivity, can potentially lead to catastrophic failure following seemingly innocuous perturbations. Carlson and Doyle hypothesized that highly-evolved networks, e.g., those involved in cell-cycle regulation, can be resistant to some perturbations while highly sensitive to others. The “robust yet fragile” duality of networks has been termed Highly Optimized Tolerance (HOT) and has been the basis of new lines of inquiry in computational and experimental biology. In this study, we tested the working hypothesis that cell-cycle control architectures obey the HOT paradigm. Three cell-cycle models were analyzed using monte-carlo sensitivity analysis. Overall state sensitivity coefficients, which quantify the robustness or fragility of a given mechanism, were calculated using a monte-carlo strategy with three different numerical techniques along with multiple parameter perturbation strategies to control for possible numerical and sampling artifacts. Approximately 65% of the mechanisms in the G1/S restriction point were responsible for 95% of the sensitivity, conversely, the G2-DNA damage checkpoint showed a much stronger dependence on a few mechanisms; ∼32% or 13 of 40 mechanisms accounted for 95% of the sensitivity. Our analysis predicted that CDC25 and cyclin E mechanisms were strongly implicated in G1/S malfunctions, while fragility in the G2/M checkpoint was predicted to be associated with the regulation of the cyclin B-CDK1 complex. Analysis of a third model containing both G1/S and G2/M checkpoint logic, predicted in addition to mechanisms already mentioned, that translation and programmed proteolysis were also key fragile subsystems. Comparison of the predicted fragile mechanisms with literature and current preclinical and clinical trials suggested a strong correlation between efficacy and fragility. Thus, when taken together, these results support the working hypothesis that cell-cycle control architectures are HOT networks and establish the mathematical estimation and subsequent therapeutic exploitation of fragile mechanisms as a novel strategy for anti-cancer lead generation.

Advocating the need of a systems biology approach for personalised prognosis and treatment of B-CLL patients

“…Each pathway is subject to an intensive study by the computational systems biology approach: modelling of the cell cycle [65][66][67][68][69][70][71][72][73], apoptosis [74][75][76], MAPK and PI3K/AKT pathways [77,78]. As these pathways are involved in cell proliferation, survival and cell death, computational models of these pathways are considered promising tools in cancer research for prediction of cancer disease progression, development of biomarkers, and drug therapy efficacy [79][80][81][82]. Henceforth, understanding the complex regulation of B-CLL disease pathogenesis, requires a strategic knowledge on the models of the cell cycle, and apoptosis that report on intrinsic and extrinsic cell signaling network.…”

“…Cell cycle modelling demonstrated that despite extensive control mechanisms in regulating phase transitions, it can lose its control and become a fragile system when variations in specific parameters of the model that affect robustness are introduced. From a clinical point of view, this fragility in the system can be referred to as cell cycle malfunction, observed as uncontrolled cell proliferation, a common phenomenon underlying many cancers [82].…”

“…Novel approaches were designed to analyze the existing models of the cell cycle to study the abnormality in its control mechanisms leading to uncontrolled cell proliferation and survival, causing diseases including solid and hematological cancers [80,82]. One of the challenges in systems biology is in determining the fragile, sensitive nodes of signaling pathways, including the cell cycle regulation, which cause the disruption of the balance between cell proliferation and death.…”

“…One of the challenges in systems biology is in determining the fragile, sensitive nodes of signaling pathways, including the cell cycle regulation, which cause the disruption of the balance between cell proliferation and death. These fragile points are suggested as control hubs within cellular signaling networks, which are extremely sensitive to mutations or the aberrant protein expression observed in cancers [82]. These fragile hubs, possessing increased sensitivity to internal perturbations, are assumed to also be sensitive to external perturbations such as drug action.…”

“…These fragile hubs, possessing increased sensitivity to internal perturbations, are assumed to also be sensitive to external perturbations such as drug action. Fragile points in signaling networks therefore represent Systems biology approach for personalised management of B-CLL promising targets for drug intervention [80][81][82]. One of the powerful methods for determining fragile nodes within cellular signaling networks is sensitivity analysis of the computational models [79,82].…”