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

I Bernard Weinstein; Andrew K Joe


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

In This Article

Mechanisms of Oncogene Addiction

We have previously proposed that the phenomenon of oncogene addiction is a consequence of the fact that the multistage process of carcinogenesis is not simply a summation of the individual effects of activation of multiple oncogenes and inactivation of multiple tumor suppressor genes.[2,3] This proposal is consistent with the fact that the proteins encoded by these genes often have multiple roles in complex and interacting networks, which display both positive and negative feedback control. The function of these proteins is also influenced by their levels of activity and the context in which they are expressed. Thus, a given oncogene can enhance cell proliferation but it can also enhance apoptosis. Furthermore, throughout the multistage carcinogenic process, the evolving cancer cell must maintain a state of homeostasis between positive-acting and negative-acting factors in order to maintain structural integrity, viability, and the capacity to replicate. For these reasons, the intracellular circuitry or 'wiring diagram' that regulates signal transduction and gene expression in cancer cells is very different, i.e., 'bizarre,' when compared to that of normal cells.[2,3] In cancer cells a given oncogene may play a more essential and qualitatively different role in a given pathway or 'module' compared with its role in normal cells. Thus, cancer cells may be much more dependent on the activity of a specific oncogene than normal cells.[3]

Within the context of disordered cell circuitry, specific mechanisms have been proposed to explain why inactivation of an oncogene might lead to selective growth inhibition, differentiation and/or apoptosis in cancer cells but not in normal cells that express the same oncogene. One explanation is that, in order to maintain homeostasis, the proliferation-enhancing effects of a specific oncogene in cancer cells might be partially buffered through negative feedback mechanisms, through increased expression of proliferation-inhibitory factors.[2] If this oncogene is then inactivated the cancer cells might suffer a relative excess of the latter inhibitory factors and thus undergo apoptosis, before a new level of homeostasis can be achieved. The apparent propensity of some cancer cells to undergo apoptosis when stressed[47] could enhance this process.

A second mechanism is based on the concept of 'synthetic lethality' originally derived from studies in lower organisms.[5] According to this concept, two genes are said to be synthetic lethal if mutation of one of the two genes is compatible with survival but mutation of both genes causes cell death.[5] For example, certain cancer cells might be highly dependent on a given oncogene because during their development they lost the function of another gene that normally performs a similar function. A drug that inhibits the activity of the oncogene would, therefore, selectively target the cancer cells and spare the normal cells. Furthermore, because of the bizarre circuitry of cancer cells, pairs of genes in cancer cells that have a synthetic lethal relationship may differ from those in normal cells, thus increasing the dependence of tumor cells on a specific oncogene. A related explanation for oncogene addiction is that, during the multistage carcinogenesis process, cancer cells become highly dependent on specific oncogenes and their related pathways because of the large numbers of mutated and inactivated genes that normally function in other pathways. This dependence could render cancer cells less adaptable than normal cells.[48]

It is of interest that only a subset of patients with NSCLC (about 10-20%) display favorable and often impressive clinical responses to the EGFR inhibitor gefitinib, and this response is often associated with tumors that have specific activating mutations in the kinase domain of EGFR. For reasons that are not understood, patients with these activating mutations are also more likely to have adenocarcinomas, be female, nonsmokers, and of Japanese origin.[35,36,37] Thus, addiction to a specific oncogene might occur only in a subset of specific types of cancers with a distinct etiology, and only when that oncogene is mutated and not simply activated. Normal EGFR activation results in induction of multiple downstream signaling pathways, some of which enhance cell proliferation while others enhance cell survival (i.e. inhibit apoptosis). An experimental study indicated that mutations in the EGFR can preferentially enhance activation of the survival, Akt-associated pathway.[49] This could explain why NSCLC cells that harbor this mutation in EGFR are highly dependent on this activated oncogene for survival. Similarly, the presence of specific deletion mutations in the EGFR gene in glioblastoma was recently shown to correlate with clinical responses to an EGFR inhibitor.[38] These data fit the paradigm that oncogene addiction can be caused by the establishment of distorted pathways of signal transduction (i.e. bizarre circuitry) during tumor development. Recent studies suggest that, in addition to point mutations in the gene encoding the EGFR, other factors could influence the sensitivity of NSCLC tumors to EGFR inhibitors, including EGFR gene amplification, the activation state of the EGFR protein, specific downstream signaling pathways, and pharmacologic factors.[50,51]


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