A stochastic model of oncogene expression and the relevance of this model to cancer therapy

Abstract

Background: Ablation of an oncogene or of the activity of the protein it encodes can result in apoptosis and/or inhibit tumor cell proliferation. Therefore, if the oncogene or set of oncogenes contributing maximally to a tumor cell's survival can be identified, such oncogene(s) are the most appropriate target(s) for maximizing tumor cell kill.

Methods and results: A mathematical model is presented that describes cellular phenotypic entropy as a function of cellular proliferation and/or survival, and states of transformation and differentiation. Oncogenes become part of the cellular machinery, block apoptosis and differentiation or promote proliferation and give rise to new states of cellular transformation. Our model gives a quantitative assessment of the amount of cellular death or growth inhibition that result from the ablation of an oncogene's protein product. We review data from studies of chronic myelogenous leukemia and K562 cells to illustrate these principles.

Conclusion: The model discussed in this paper has implications for oncogene-directed therapies and their use in combination with other therapeutic modalities.

Figure 1

Oncogenes can affect multiple cellular pathways, which result in modulating proliferation and apoptosis. Depicted here are three oncogenes. Oncogene 2's activity overlaps with the activities of the other two. Therefore, ablation of oncogene 2's activity would not result in any measurable change in proliferation or apoptosis.

Figure 2

Bcr-Abl modulates up to four cellular pathways, but because of the interdependence of these pathways, we conclude that 3 pathways best represent the number of transformed states incurred by the oncogene's behavior.

Figure 3

A normal cell, N, is transformed thereby increasing its phenotypic entropy. When the oncogene inhibitor is applied to the transformed cell, T, the cell maintains constant phenotypic entropy and therefore does not return to its normal state. As a result of the loss of the oncogene's protective actions, the transformed cell, Ti, is less adapted to its environment and undergoes either growth inhibition or apoptosis.