oncogene addiction versus oncogene amnesia: …...perhaps the most compelling evidence that cancer...

Oncogene Addiction versus Oncogene Amnesia: Perhaps More than

Just a Bad Habit?

Dean W. Felsher

Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, California

Abstract

Cancer is a multistep process whereby genetic events thatresult in the activation of proto-oncogenes or the inactivationof tumor suppressor genes usurp physiologic programsmandating relentless proliferation and growth. Experimentalevidence surprisingly illustrates that the inactivation of even asingle oncogene can be sufficient to induce sustained tumorregression. These observations suggest the hypothesis thattumors become irrevocably addicted to the oncogenes thatinitiated tumorigenesis. The proposed explanation for thisphenomenon is that activated oncogenes result in a signalingstate in which the sudden abatement of oncogene activitybalances towards proliferative arrest and apoptosis. Indeed,substantial evidence supports this hypothesis. Here, wepropose an alternative, although not necessarily mutuallyexclusive, explanation for how oncogenes initiate and sustaintumorigenesis. We suggest that oncogene activation initiatestumorigenesis precisely because it directly overrides physio-logic programs inducing a state of cellular amnesia, not onlyinducing relentless cellular proliferation, but also bypassingcheckpoint mechanisms that are essential for cellular mor-tality, self-renewal, and genomic integrity. Because no singleoncogenic lesion is sufficient to overcome all of thesephysiologic barriers, oncogenes are restrained from inducingtumorigenesis. Correspondingly, in a tumor that has acquiredthe complete complement of oncogenic lesions required toovercome all of these safety mechanisms, the inactivation of asingle oncogene can restore some of these pathways resultingin proliferative arrest, differentiation, cellular senescence,and/or apoptosis. Thus, oncogenes induce cancer becausethey induce a cellular state of enforced oncogenic amnesia inwhich, only upon oncogene inactivation, the tumor becomesaware of its transgression. [Cancer Res 2008;68(9):3081–6]

The Rise and Fall of Cancer through OncogeneInactivation

Cancer is generally thought of as a multistep genetic disorder (1).Pathopneumonic genetic lesions are associated with the perturba-tion of the function of specific proto-oncogenes that are thehallmarks of unique cancers. Hence, it seemed reasonable topresume that the repair or inactivation of these mutant geneproducts could reverse the process of tumorigenesis. However,because cancers are thought to be quite genetically complicated, itwas not necessarily the case that fixing any specific mutant geneproducts would be sufficient to influence neoplasia. A priori,

several possible outcomes were likely from the inactivation of asingle oncogene: no effect, complete regression, or a partial loss ofneoplastic features (Fig. 1).Perhaps the most compelling evidence that cancer can be

reversed through oncogene inactivation came from studiesperformed using conditional mouse models (2–4). Using differentmethods, several studies dramatically illustrated that a cancerinitiated by a specific oncogene underwent sustained tumorregression upon the inactivation of that oncogene (5–14). Hence,it was concluded that, at least in these somewhat experimentallycontrived circumstances, cancer is a reversible process.From work in transgenic mouse models, several general principles

emerged, as we have summarized previously (Fig. 2; refs. 15–19).The suppression of oncogene overexpression is sufficient to inducetumor regression, thus it is not necessary to inactivate the phy-siologic function of the corresponding proto-oncogene to inducetumor regression. The consequences of oncogene activation forthe initiation of tumorigenesis and the consequences of oncogeneinactivation for the reversal of tumorigenesis depend on the type oftumor and the cellular and genetic context. Thus, inactivation of anoncogene variously induces proliferative arrest, differentiation,apoptosis, and/or senescence. In some cases, brief oncogene inac-tivation is sufficient to induce sustained tumor regression, but inother cases, resumption of oncogene activity restores neoplasia.Hence, upon oncogene inactivation, cancer could be ‘‘revoked’’permanently, or in other cases, cancer cells could become ‘‘dormant.’’Cancers can escape dependence on oncogenes by acquiring othergenetic events. Collectively, these observations suggested that therewas reason for optimism and that it would be possible to definespecific rules by which oncogenic activation initiates and maintainstumorigenesis.Then, the discovery of Gleevec made it convincingly apparent

that the targeted inactivation of oncogenes was also likely to be asuccessful therapeutic approach for at least some human cancers.Gleevec targets several tyrosine kinases, including BCR-ABL andc-kit, and was shown to be able to successfully therapeutically treatpatients with chronic myelogenous leukemia and gastrointestinalstromal tumors (20). When tumors recurred after prolongedtreatment with Gleevec, it was shown that there were specificmutations in the ABL that prevented the inactivation of its kinaseactivity (21). Thus, there was evidence that fixing a brokenoncogene could reverse a human cancer. Hence, we entered an eraof targeted therapeutics in which genetic principles may guide ustowards the development of effective therapies for cancer.From these results in experimental models and observations in

patients, should we be so optimistic that cancers could generallybe treated through targeted therapies? Although it seems thatshutting down oncogenes has a dramatic phenotypic outcome,the mechanism by which this works, or why in some cases itfails to work, remains obscure. To date, targeted therapies, evenwhen initially effective, eventually generally fail. Indeed, we areconsumed by an interest in targeting specific gene products for

Requests for reprints: Dean W. Felsher, Division of Oncology, Departments ofMedicine and Pathology, Stanford University School of Medicine, Stanford, CA. Phone:650-498-5269; Fax: 850-725-1420; E-mail: [email protected].

I2008 American Association for Cancer Research.doi:10.1158/0008-5472.CAN-07-5832

www.aacrjournals.org 3081 Cancer Res 2008; 68: (9). May 1, 2008

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the treatment of cancer without any clear insight into when orwhy this is a valid approach. Although one could argue that themechanism is of less importance than the outcome, as has beengenerally presumed now by academia and industry, an understand-ing of the mechanisms by which oncogene inactivation inducestumor regression would seem important not just as an intellectualexercise, but also as a practical necessity for developing rationalecures for cancer.

Oncogene Addiction: A New Insight intoTumorigenesis

When we and others first described that MYC inactivation‘‘reversed’’ tumorigenesis, our explanation was somewhat prosaicnot because we did not have an idea of the possible mechanisms, ofwhich we proposed several, but we were aware that, at the time, itwas hard enough to be certain of the observation. We simplypointed out that when a gene was broken, and that it caused acancer, then fixing that gene would restore the tumor cell back toits previous physiologic state which, in many cases, would result inarrest, differentiation, and/or apoptosis. Hence, cancer couldliterally be reversed.However, even at that time, we were very aware that our results

were thus far actually in discordance with some of our ownfindings, and that this discordance actually implicated a possibleunifying mechanism that I will explain. Most pointedly, we had justdescribed that MYC could induce cancer through a hit and runmechanism through the induction of genomic damage (22). A

wealth of additional observations even more convincingly illus-trated that many oncogenes are likely to contribute to tumorigen-esis by inducing various types of genomic damage includingpolyploidy, aneuploidy, endoreduplication, DNA breaks, and trans-locations (23–25). Oncogenes have been shown to induce genomicdamage by several mechanisms including the direct disruption ofcheckpoints that regulate DNA replication and DNA double-strandbreak repair (22–27). Oncogene activation has also been observedto induce genomic instability in vivo in murine models (28), andeven more importantly, in human tissues (29). Thus, ourobservation that shutting off MYC casually resulted in sustainedand complete tumor regression was initially a surprise. However,we recognized that perhaps oncogene inactivation was inducingtumor regression precisely because tumors could now recognizethat they are damaged (27).Then, the first general conceptual insight for the mechanism of

reversal of cancer following oncogene inactivation was provided byWeinstein, who argued that tumors were addicted to oncogenes. Inthis model, oncogenes would necessarily induce a distinct andcomplex signaling state which would result in the activation ofphysiologic programs that would attempt to counteract the effectsof the oncogene on proliferation and apoptosis (30, 31). Hence,when the oncogene was inhibited, these signaling programs wouldbe unopposed resulting in synthetic lethality, and tumors would diebecause they had been addicted to the oncogene that initiated theirpathologic state.Oncogene addiction provides a satisfying explanation for much of

what has been observed experimentally. The term is intellectually

Figure 1. Many possible outcomes to oncogene inactivation: no effect, complete, or partial tumor reversion. Tumor death, dormancy, differentiation, or relapse.

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very appealing and thus many investigators, certainly including me,have embraced this concept in broad scientific forums. In particular,oncogene addiction seems to precisely explain the general obser-vation that oncogene inactivation particularly results in the death oftumor cells as opposed to normal cells. However, the model providesa vague explanation for the observation that the consequences ofoncogene inactivation are different for different tumors and differentoncogenes. Also, the model, in particular, does not seem to addressthe notion that ‘‘self-renewal’’ has emerged as one of the mostfundamental epigenetic characteristics of a cancer, and a propertythat is not necessarily maintained by all of the cells within a tumor(32–35). The converse of self-renewal is ‘‘cellular senescence’’ andnew evidence from my group hints that oncogene inactivation oftumors may generally induce cellular senescence (36). Therefore,pathways that regulate self-renewal, immortality, and senescence areparticularly important features associated with oncogene activationand the initiation of tumorigenesis, the mechanisms that restraintumor initiation, and the phenomena of tumor maintenance.Although cellular senescence may be an outcome of oncogeneaddiction, there seem to be more direct explanations for whyoncogene inactivation results in the arrest, apoptosis, and senes-cence of tumor cells. In addition, oncogene addiction does notaccount for non-cell autonomous host mechanisms that contributeto tumor regression. Lastly, oncogene addiction does not addresshow mechanisms of tumor regression following oncogene inactiva-

tion may be more directly related to the mechanisms by whichoncogene initiate and are restrained from causing tumorigenesis.

Oncogenic Amnesia: the Dr. Jekyll and Mr. HydeModel of Cancer

We propose, as a possible unifying explanation for howoncogenes initiate and are restrained from causing tumorigenesis,and why oncogene inactivation induces tumor regression, that thisis a direct consequence of the fact that specific oncogenes play adirect role in the regulation of physiologic safety switches thatregulate mortality/self-renewal, differentiation, and/or DNA repair.Our model can also accommodate the notion that cell autonomoushost mechanisms play a role in the mechanisms by whichoncogenes initiate and sustain tumorigenesis.It is axiomatic that many oncogenes contribute to tumorigenesis

by inducing unrestrained cellular proliferation and growth, and byovercoming physiologic controls or safety switches. Analogously,oncogene activation has been shown to be restrained from causingtumorigenesis because this results in genotoxic stress—actualgenomic damage—and that this stress activates cellular mecha-nisms that restrain any individual oncogene from causingtumorigenesis by activating cellular programs that induce prolifer-ative arrest, cellular senescence, and apoptosis (37). Hence, cancer ispostulated to arise only after these physiologic barriers have been

Figure 2. Oncogene inactivation has been observed to have different outcomes in different types of tumors including proliferative arrest, differentiation, apoptosis, and/or cellular senescence. Although the consequences are different for each type of tumor, cellular senescence seems to be a convergent common mechanism.

Oncogene Addiction versus Oncogene Amnesia




overcome. Indeed, one of the most characteristic features of canceris that they not only exhibit autonomous proliferation and growthbut exhibit genomic instability, suggesting that they have lostcontrol of regulatory mechanisms that maintain genomic integrity.As previouslymentioned, oncogeneshave been shown to contribute

to genomic damage precisely because they override physiologiccheckpoints that regulate DNA replication and repair. Yet despitethese pervasive genomic disruptions that in normal cells wouldprompt an aggressive response inducing proliferative arrest, senes-cence, and/or apoptosis, tumors seem to be oblivious or amnesic totheir genomic disruption. For a tumor to arise, these physiologic safetyswitches must be shut off, and no single oncogenic lesion is sufficientto do this. Thus, when an individual oncogene is activated, this doesblock some of the safety switches and this indeed can cause genotoxicstress, which we think is actually DNA damage, and this activates theother safety switches and the cells arrest, die, or undergo senescence.Thus, for cancer to arise, other ‘‘genetic events’’ must occur to

block enough of the other safety switches to correspondingly blockthe arrest/senescence/apoptosis response. Then, it may bepresumed that by inactivating one of the oncogenes, you wouldnecessarily restore at least some of these safety switches that hadbeen ‘‘epigenetically’’ blocked by the ‘‘genetic’’ oncogenic event,awakening from their slumber the relevant physiologic programs.Indeed, upon oncogene inactivation, tumors exhibit a restoration

of physiologic programs that is analogous to a physiologic responseto DNA damage: proliferative arrest, differentiation, apoptosis, and/or senescence. At first glance, this seemed a paradox, for if cellcycle arrest, apoptosis, and cellular senescence are the barriers tooncogene initiation of tumorigenesis, then shouldn’t these path-ways be abrogated in an established tumor, and hence, oncogeneinactivation should not result in arrest, apoptosis, or senescence?However, the explanation could be that oncogene inactivation mayinduce tumorigenesis precisely because these gene products oftenplay a direct role in the regulation of physiologic programs thatgovern not only cell cycle checkpoint mechanisms but also self-renewal/mortality and senescence programs.Hence, oncogene inactivation would necessarily uncover precise-

ly the specific physiologic programs that the oncogene antagonizedto promote immortality/self-renewal. In some cases, this maysimply restore physiologic programs such as cellular differentiation.In many cases, oncogene inactivation would then permit tumors torecognize that they are genomically damaged and result in cellularsenescence (Fig. 3). Oncogene inactivation can restore thecheckpoints that it had blocked. In some cases, this results in thepermanent ability of tumor cells to attain a neoplastic phenotype.The circumstance is analogous to the classic story of Dr. Jekyll

and Mr. Hyde. As Mr. Hyde, under the influence of the potionof oncogenic activation, tumors behave without moral restraint—

Figure 3. Oncogenic amnesia: the Dr. Jeckyll and Mr. Hide model of cancer. Cancers exhibit autonomous behavior resulting in immortality, self-renewal, andproliferation. Cancers influence the microenvironment to support tumorigenesis. Oncogene inactivation restores physiologic safety switches and results in proliferativearrest, differentiation, apoptosis, and cellular senescence, as well as the restoration of a physiologic microenvironment including the suppression of angiogenesis.

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autonomous and out of control with regards to the destructionof themselves or others. Then, as this consuming potion wearsout, upon oncogene inactivation, there is a restoration of the abilityof tumor cells to become aware of their genomic disruptionand with self-consciousness. Aware of his misdeeds as Mr. Hyde,Dr. Jekyll in moral indignation, feels compelled to permanentlydestroy himself through death. Of course, our observationssuggest that Dr. Jekyll also has two other possible outcomes, tolearn from his ways and mature into a well-differentiated morerestrained scientist; or under the distress of moral indignation,rapidly ages into a senescent and now permanently innocuoussenior colleague.The important discriminating point of oncogenic amnesia and

the oncogene addiction models is that tumor regression followingoncogene inactivation in the former is a direct consequence of therestoration of physiologic pathways. Thus, tumorigenesis is‘‘restrained’’ because oncogenes block only some but not all ofthe safety switches which results in DNA damage and a physiologicresponse. Cancer is reversed because oncogene inactivationrestores the programs that were blocked by that particularoncogene. Importantly, this model recognizes that the completeinactivation of an oncogene is not required to induce tumorregression, but simply the restoration of the oncogene tophysiologic levels so that physiologic programs are resumed. Theconsequences of oncogene inactivation would be predicted to bedifferent depending on the particular oncogene and the particulargenetic and epigenetic features of a tumor. Tumors that weredefective for other reasons in apoptosis pathways would be morelikely to differentiate or senesce. Tumors defective in genes that areinvolved in mediating many pathways would exhibit greatlyimpaired or transient tumor regression.

Oncogene Addiction/Amnesia Cancer Stem Cellsand the Microenvironment

No single model will account for all observations and there isunlikely to be any one explanation for how oncogenes initiate orsustain tumorigenesis. However, considering cancer to be aconsequence of ‘‘oncogenic amnesia’’ may provide a context forunderstanding why self-renewal/immortality/senescence seems tobe some of the most important cellular programs involved in theinitiation, restraint, and reversal of tumorigenesis. In addition, it isimportant to recognize that host-dependent tumor extrinsicmechanisms are likely to play a fundamental role in themechanisms by which cancers arise, are prevented, and regress.How does this model accommodate the ‘‘cancer stem cell

hypothesis?’’ The term cancer stem cell is widely agreed to be asomewhat misleading description of a phenomena which does notnecessarily imply that the cells are stem cells, but rather, that only aportion of the tumor cells are immortal and self-renew indefinitely.Many of the tumor cells spontaneously lose the capacity for endless

replication/self-renewal. My proposed model would account for thephenomena of cancer stem cells by suggesting that in these cellsthe programs that oppose self-renewal, such as cellular senescenceare intrinsically turned off, most likely via epigenetic mechanisms.Many different possible mechanisms are likely to operate. Some

oncogenic lesions are likely to be more intimately related to self-renewal programs, which seems to be the likely case for MYC (38). Itremains to be seen if other oncogenes also maintain tumorigenesisthrough the regulation of self-renewal and senescence. We havereported evidence that this is true for MYC and RAS, as well as inlymphoma, hepatocellular carcinoma, and osteosarcoma (36). Themolecular basis for the ‘‘safety switches’’ that are being blocked byMYC and other oncogenes will have to be identified. We have foundevidence suggesting that p15, p16, RB, and p53 are logicalcandidates (36). However, it will be important to more broadlysubstantiate whether oncogene inactivation induces tumor regres-sion both in other model systems and in human tumors.Importantly, any model of tumor regression must incorporate

the idea that oncogene inactivation is likely to induce tumorregression not only from tumor cell intrinsic mechanisms, but alsothrough host mechanisms of tumor suppression (Fig. 3). Manydifferent mechanisms are likely, but we have recently notedthat oncogene inactivation results in tumor regression both throughtumor cell intrinsic and host-dependent mechanisms includingangiogenesis (39). Hence, oncogene inactivation in the tumormay not only be achieved by reawakening the tumor’s normalcellular physiologic programs, but it seems to cause the tumorto send the correct cues to the host to restore the physiologicmicroenvironment.As a final point, whether oncogene addiction or amnesia best

defines the fate of cancers upon oncogene inactivation, it would bewise to dissect the molecular pathways that define the phenotypicconsequences of oncogene inactivation. By looking at differentoncogenes and seeing to what extent these pathways are similar ordifferent, it should become manifest if there are discrete programsassociated with particular oncogenes, which epigenetic variablesare most important, and/or the constellation of genetic events thatdefine a tumor. By understanding these mechanisms, it will morelikely be possible to utilize targeted therapeutics more generally asan effective therapy for cancer. Only with such insights willtargeted therapies realize their full potential to be more effectiveover existing empiric therapies.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

Received 10/10/2007; accepted 2/17/2008.Grant support: Research grants from the NIH, the Lymphoma and Leukemia

Society, the Burroughs Wellcome Fund, and the Damon Runyon Foundation.

Oncogene Addiction versus Oncogene Amnesia


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We appreciate the thoughtful article by Dr. Dean Felsher.Indeed, his seminal studies on conditional expression ofoncogenes in mouse models played an important role in ourformulation of the concept of oncogene addiction. We agree withhim that multiple mechanisms may explain the phenomenon ofoncogene addiction, depending on the particular system beingstudied. This is not surprising in view of the diverse functions ofindividual oncogenes, the coexistence in cancer cells of abnor-malities in multiple oncogenes and tumor suppressor genes, andthe context of the tissue in which the tumor developed. Hissuggestion that inactivation of specific oncogenes can restorecheckpoint mechanisms (‘‘safety switches’’), that are essential forcellular mortality, self-renewal, and genomic integrity is provoc-ative. However, except for DNA damage responses, at the presenttime, the biochemical mechanisms that mediate these check-points are not well defined. Thus, his term ‘‘oncogene amnesia’’ isvague because it is not clear what was forgotten. Moreover,restoration or resumption of these physiologic programs impliesthat the original pathways which regulate cellular differentiation,senescence, and apoptosis are intact. This does not appear to beconsistent with the bizarre circuitry, genomic instability, and

aneuploidy that progressively develop during multistage carcino-genesis. Nevertheless, his hypothesis should stimulate furtherresearch on these checkpoints and their relevance to oncogeneaddiction.We agree with Dr. Felsher’s emphasis on the importance of

changes in both self-renewal mechanisms and cellular senes-cence in the response of cancer cells to oncogene inactivation.His recent studies indicating that ‘‘oncogene inactivation resultsin tumor regression both through tumor cell intrinsic and host-dependent mechanisms including angiogenesis’’ also provide newinsights into the phenomenon of oncogene addiction. Hopefully,further studies on the mechanisms by which oncogene addictionaffects tumor-host interactions will also reveal more effectivemethods for molecular targeted cancer therapy.

I. Bernard WeinsteinAndrew JoeHerbert Irving Comprehensive Cancer Center andDepartment of Medicine, Columbia University Medical Center,New York, New York

Response

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