Mechanisms of Disease: Oncogene Addiction-A Rationale for Molecular Targeting in Cancer Therapy

I Bernard Weinstein; Andrew K Joe

Disclosures

Nat Clin Pract Oncol. 2006;3(8):448-457. 

In This Article

Multistage Carcinogenesis and the Concept of Oncogene Addiction

It is now an axiom in oncology that human cancers often evolve through a multistage process that extends over decades. The marked increase in molecular biology studies within the past three decades has revealed that this multistage process is driven by the progressive accumulation of mutations and epigenetic abnormalities in expression of multiple genes that have highly diverse biochemical functions. Malignant carcinomas of the lung, colon, breast, and other organ sites often display mutations in multiple oncogenes and tumor suppressor genes, harbor epigenetic abnormalities that result in increased or decreased expression of hundreds of genes, and contain chromosomal abnormalities that include aneuploidy and loss of heterozygosity at numerous loci; this topic has been comprehensively reviewed.[1,2] It is therefore surprising that despite this extensive disruption in the genomes of cancer cells, there are several examples in both experimental systems ( Table 1 and Table 2 ) and in patients with cancer ( Table 3 ) whereby the reversal of only one or a few of these abnormalities can profoundly inhibit the growth of cancer cells and, in some cases, lead to improved survival rates. A few years ago we described this phenomenon as 'oncogene addiction,' to emphasize the apparent dependency of some cancers on one or a few genes for maintenance of the malignant phenotype.[2,3] The purpose of this review is to summarize current experimental and clinical evidence for the concept of oncogene addiction and to describe molecular mechanisms that may explain this phenomenon. In addition, we discuss its relevance to the development of more effective and specific forms of cancer prevention and therapy, by targeting the specific genes that are critical for maintenance of the malignant phenotype of specific types of human cancer. This approach merges with the current development of novel molecular targeted agents for cancer chemoprevention and therapy. Related reviews on this subject have recently been published.[4,5]

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