Oncogene addiction: setting the stage for molecularly targeted cancer therapy

Abstract

In pugilistic parlance, the one-two punch is a devastating combination of blows, with the first punch setting the stage and the second delivering the knock-out. This analogy can be extended to molecularly targeted cancer therapies, with oncogene addiction serving to set the stage for tumor cell killing by a targeted therapeutic agent. While in vitro and in vivo examples abound documenting the existence of this phenomenon, the mechanistic underpinnings that govern oncogene addiction are just beginning to emerge. Our current inability to fully exploit this weakness of cancer cells stems from an incomplete understanding of oncogene addiction, which nonetheless represents one of the rare chinks in the formidable armor of cancer cells. 'Oncogene addiction': defining the termCancer is, an old adage goes, actually a hundred diseases masquerading as one. In our fight against this dreaded disease, casualties abound and successes are few and far between. Given the bewildering diversity of causality, it is gratifying to realize that painstaking investigation over the past 50 years has highlighted some common themes in the genesis and progression of cancer (Hanahan and Weinberg 2000). These commonalities offer a glimmer of hope that potential targets may exist within the cancer cell that can be exploited in combating these diseases. The first unifying theme is that cancer is caused by a handful of "rogue" corrupted cellular genes, designated oncogenes, that hijack the cell, causing it to survive indefinitely and proliferate aberrantly. The second unifying theme is that the genesis and progression of a tumor is governed by the activation of specific oncogenes and inactivation of tumor suppressor genes, and the stochastic accumulation of these genetic alterations progressively drives the evolution of cancer from a benign expansion of cells to an invasive and metastatic tumor. This is well illustrated by the example of colorectal cancer (Kinzler and Vogelstein 1996).On the face of it, this would suggest that cancer is a "moving target" that may be impossible to destroy. However, recently, a third common theme has begun to emerge that offers cause for guarded optimism. This phenomenon, referred to as "oncogene addiction," a term first coined in 2000 by Bernard Weinstein, reveals a possible "Achilles' heel" within the cancer cell that can be exploited therapeutically (Weinstein 2000(Weinstein , 2002Weinstein and Joe 2006). In its simplest embodiment, oncogene addiction refers to the curious observation that a tumor cell, despite its plethora of genetic alterations, can seemingly exhibit dependence on a single oncogenic pathway or protein for its sustained proliferation and/or survival. At first glance, the fact that a tumor cell can exhibit dependency on a single protein that contributed to the malignant phenotype at some point in its history may seem to be trivial. However, the fact that inactivating the normal counterpart of such oncogenic proteins in normal tissues is often tolerated without obvious consequence highlights the...

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