Mechanisms of Disease: oncogene addiction—a rationale for molecular targeting in cancer therapy

Abstract

The oncogene addition concept was established to explain how some cancers that contain multiple genetic, epigenetic, and chromosomal abnormalities are dependent on or are “addicted” to one or more genes for both maintenance of the malignant phenotype and cell survival. Weinstein and Joe summarize current experimental and clinical evidence of this concept and describe some of the molecular mechanisms of this phenomenon. The use of molecular targeted agents in combination with cytotoxic agents, and the advances in systems biology and network theory can help to facilitate an optimal treatment approach. There has been considerable progress in the systemic treatment of cancer because of the rapid development and clinical application of molecular targeted agents. Although patients with a particular type and stage of cancer are often treated as a single group, more-specific therapy is being considered, as subsets of these patients who are more likely to benefit from treatment with particular agents are being identified. We previously introduced the concept of 'oncogene addiction' to explain how some cancers that contain multiple genetic, epigenetic, and chromosomal abnormalities are dependent on or 'addicted' to one or a few genes for both maintenance of the malignant phenotype and cell survival. Thus, reversal of only one or a few of these abnormalities can inhibit cancer cell growth and in some cases translate to improved survival rates. This review summarizes current experimental and clinical evidence for the concept of oncogene addiction and describes molecular mechanisms that may explain this phenomenon. In addition, we discuss how high-throughput screening methods, including gene-expression profiling and proteomics, and emerging methods for analyzing complex cellular networks can be used to identify the state of oncogene addiction, i.e. the 'Achilles' heel,' in specific cancers. Finally, we discuss the use of molecular targeted agents in combination with other anticancer agents as a strategy to optimize therapy and prevent disease recurrence.