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

Nature Clinical Practice Oncology volume 3, pages 448–457 (2006)Cite this article

Abstract

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.

Key Points

  • 'Oncogene addiction' describes the phenomenon by which some cancers that contain multiple genetic and epigenetic abnormalities remain dependent on (addicted to) one or a few genes for both maintenance of the malignant phenotype and cell survival

  • Evidence that supports the concept of oncogene addiction has now been obtained in three diverse systems: 1) genetically engineered mouse models of human cancer, 2) mechanistic studies in human cancer cell lines, and 3) clinical trials with specific molecular targeted agents

  • 'Network theory' and other techniques of systems biology may provide methods for analyzing the entire circuitry of cancer cells and thus facilitate identification of pathways of oncogene addiction in specific types of human cancer

  • These insights will guide the development and clinical application of novel molecular targeted agents

  • Treatment regimens that combine molecular targeted agents with other anticancer agents could provide the optimal strategy for treating and preventing cancer

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Acknowledgements

This work was supported by awards to IBW from the National Foundation for Cancer Research, the Entertainment Industry–National Colorectal Research Alliance, and the TJ Martell Foundation, and awards to AKJ from the National Cancer Institute (5K23CA101669) and the National Institutes of Health (MO1-RR00645).

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Authors and Affiliations

  1. Frode Jensen Professor of Medicine, Genetics and Development, and Public Health at the College of Physicians and Surgeons, Columbia University, New York

    I Bernard Weinstein & Andrew K Joe

  2. Florence Irving Assistant Professor of Clinical Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    I Bernard Weinstein & Andrew K Joe

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Correspondence to I Bernard Weinstein.

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Weinstein, I., Joe, A. Mechanisms of Disease: oncogene addiction—a rationale for molecular targeting in cancer therapy. Nat Rev Clin Oncol 3, 448–457 (2006). https://doi.org/10.1038/ncponc0558

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