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The Dynamics of the Cell Signaling Network; Implications for Targeted Therapies

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Targeted Therapies

Part of the book series: Molecular and Translational Medicine ((MOLEMED))

Abstract

Molecular targeted therapies against signaling molecules that are active in ­cancer have shown only incomplete and temporary clinical benefit when used as single agents. One explanation for the limited clinical benefit is that extracellular signals are transmitted through a network of proteins rather than through hierarchical signaling pathways; a network inhibition of a single component is insufficient to have dramatic effects on the treatment of cancer since the biological outcome of signals propagated through a network is inherently more resistant to perturbations. In this chapter, we discuss the major mechanisms of resistance to targeted therapeutics using alterations in the cell signaling network. We present specific examples of redundant (intrinsic) and compensatory (acquired) signaling leading to resistance. These include the redundant mechanisms of (1) mutation in a downstream effector rendering inhibition of an upstream activator ineffective and (2) the presence of redundant signaling pathways regulating cancer cell growth as well as the compensatory resistance mechanisms including (3) the upregulation of a second signaling pathway which substitutes for the targeted pathway, and (4) loss of feedback control when inhibiting a downstream effector which facilitates activation of upstream components of the signaling pathway. We also discuss the general implications of the cell signaling network on resistance and the design of effective drug treatments.

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Acknowledgments

I would like to thank Dr. Neal Rosen for helpful discussions and input on the subject and Dr. Debra McMahon for critically reading the manuscript.

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  1. Department of Microbiology and Cancer Center, University of Virginia, Charlottesville, VA, 22908, USA

    Daniel Gioeli

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  1. Health System, Deptartment of Microbiology and Cancer C, University of Virginia, Charlottesville, 22908-0734, Virgin Islands, USA

    Daniel Gioeli

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Gioeli, D. (2011). The Dynamics of the Cell Signaling Network; Implications for Targeted Therapies. In: Gioeli, D. (eds) Targeted Therapies. Molecular and Translational Medicine. Humana Press. https://doi.org/10.1007/978-1-60761-478-4_2

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