Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction Ji Luo, Nicole L. Solimini, Stephen J. Elledge  Cell  Volume 136, Issue 5, Pages 823-837 (March 2009) DOI: 10.1016/j.cell.2009.02.024 Copyright © 2009 Elsevier Inc. Terms and Conditions

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. Cell 2009 136, 823-837DOI: (10.1016/j.cell.2009.02.024) Copyright © 2009 Elsevier Inc. Terms and Conditions

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. Cell 2009 136, 823-837DOI: (10.1016/j.cell.2009.02.024) Copyright © 2009 Elsevier Inc. Terms and Conditions

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. Cell 2009 136, 823-837DOI: (10.1016/j.cell.2009.02.024) Copyright © 2009 Elsevier Inc. Terms and Conditions