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, 136 (5), 823-37

Principles of Cancer Therapy: Oncogene and Non-Oncogene Addiction

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Principles of Cancer Therapy: Oncogene and Non-Oncogene Addiction

Ji Luo et al. Cell.

Erratum in

  • Cell. 2009 Aug 21;138(4):807

Abstract

Cancer is a complex collection of distinct genetic diseases united by common hallmarks. Here, we expand upon the classic hallmarks to include the stress phenotypes of tumorigenesis. We describe a conceptual framework of how oncogene and non-oncogene addictions contribute to these hallmarks and how they can be exploited through stress sensitization and stress overload to selectively kill cancer cells. In particular, we present evidence for a large class of non-oncogenes that are essential for cancer cell survival and present attractive drug targets. Finally, we discuss the path ahead to therapeutic discovery and provide theoretical considerations for combining orthogonal cancer therapies.

Figures

Figure 1
Figure 1. The Hallmarks of Cancer
In addition to the six hallmarks originally proposed by Hanahan and Weinberg (top half, white symbols) and evasion of immune surveillance proposed by Kroemer and Pouyssegur, we propose a set of additional hallmarks that depict the stress phenotypes of cancer cells (lower half, colored symbols). These include metabolic stress, proteotoxic stress, mitotic stress, oxidative stress, and DNA damage stress. Functional interplays among these hallmarks promote the tumorigenic state and suppress oncogenic stress. For example, the utilization of glycolysis allows tumor cells to adapt to hypoxia and acidify its microenvironment to evade immune surveillance. Increased mitotic stress promotes aneuploidy, which leads to proteotoxic stress that requires compensation from the heat shock response pathway. Elevated levels of reactive oxygen species result in increased levels of DNA damage that normally elicits senescence or apoptosis but is overcome by tumor cells.
Figure 2
Figure 2. Examples of Non-oncogene Addictions in Cancer Cells
The tumorigenic state results in a variety of alterations (shown on top), which are related to the hallmarks described in Figure 1. These alterations give rise to a number of potentially deleterious circumstances or vulnerabilities (detailed in the bottom half) that could be lethal to the tumor cells if left unchecked. The existence of stress support pathways (shown in red) help suppress this lethality. Many of these pathways are examples of non-oncogene addiction (NOA), and therapeutics that interfere with their functions could display synthetic lethality with the tumor genotype/phenotype.
Figure 3
Figure 3. The Combinatorial Filter of Orthogonal Cancer Therapies
A tumor consists of genetically distinct subpopulations of cancer cells (represented by the different cell shapes), each with its own characteristic sensitivity profile to a given therapeutic agent. Each cancer therapy can be viewed as a filter that removes a subpopulation of cancer cells that are sensitive to this treatment while allowing other insensitive subpopulations to escape. This escape occurs as a result of suppressor mutations that occur at a given frequency (v) unique to each therapy and tumor type. By combining therapies with orthogonal modes of action, a combinatorial filter can be set up to minimize the recurrence index (RI) of the cancer. N represents the total number of cancer cells in the tumor. A combination of orthogonal therapies that result in RI < 1 would greatly enhance the likelihood of preventing tumor recurrence.

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