perspectives - CCIS - Stanford University

PERSPECTIVES OPINION

Cancer revoked: oncogenes as therapeutic targets Dean W. Felsher Recent findings show that even the brief inactivation of a single oncogene might be sufficient to result in the sustained loss of a neoplastic phenotype. It is therefore possible that the targeted inactivation of oncogenes could be a specific and effective treatment for cancer. So why does oncogene inactivation cause tumour regression and will this be a generally successful approach for the treatment of human neoplasia?

Tumorigenesis is generally associated with the activation of oncogenes. The development of pharmacological agents that inactivate or repair these mutant gene products might therefore be a specific and effective treatment for cancer; however, there are many potential problems. As cancer is caused by multiple genetic events, the inactivation of a single mutant gene product might not be sufficient to induce tumour regression. Even if oncogene inactivation initially induces tumour regression, tumours are often genomically unstable and might readily compensate by acquiring additional genetic events. Finally, even when the pharmacological inactivation of an oncogene does successfully induce tumour regression, a tumour could relapse following the cessation of therapy. There are many reasons why the inactivation of an oncogene might fail to induce tumour regression. Despite these theoretical concerns, increasing experimental evidence — in particular, using transgenic mouse models — shows that the targeted, and perhaps even the brief,

inactivation of a single oncogene can be a specific and effective therapy for cancer. Several groups have generated transgenic mice that conditionally express oncogenes to show that the inactivation of that oncogene is sufficient to induce tumour regression1–8 (TABLE 1). In addition, recent experience in humans indicates that it could be possible to use pharmacological agents that inactivate oncogenes to treat at least some types of human cancer9,10. Tumours seem to require the persistence of oncogene activation to sustain their neoplastic phenotype. Even brief oncogene inactivation has, in one case, been shown to result in the sustained loss of a neoplastic phenotype3. Cancers can remain ‘addicted’ to the oncogenes that initiated tumorigenesis11. Three questions are raised by these observations. What is the evidence that oncogene inactivation induces tumour regression? Why does this occur? And when might the targeted inactivation of oncogenes be useful for the treatment of human neoplasia? Consequences of oncogene inactivation

Theoretical. Tumorigenesis is generally thought to be a multi-step process, in which genetic events that activate oncogenes or inactivate tumour-suppressor genes are sequentially acquired. Each event is thought to confer specific malignant features — such as cell-autonomous proliferation, cellular immortalization, induction of angiogenesis, blocked differentiation, genomic destabilization and metastasis — and the summation of these genetic events is thought to be responsible for the neoplastic phenotype of

NATURE REVIEWS | C ANCER

a tumour. The targeted inactivation or repair of specific mutant gene products could, under at least some circumstances, remove these malignant phenotypes and, in effect, reverse the process of tumorigenesis. However, inactivation of an oncogene would not necessarily cause tumour regression — many different outcomes would be possible (FIG. 1). First, there could be no effect. Tumours can even become rapidly independent of an oncogenic event that was essential for the induction of tumorigenesis. Some oncogenes could be dispensable after crucial events have been acquired. For example, if an oncogene induces genomic destabilization, it could promote tumorigenesis by facilitating the acquisition of other genetic events that are then responsible for neoplasia. Second, tumours could lose the neoplastic characteristics that are conferred by that particular oncogene. For example, inactivation of an oncogene that contributes to the invasive properties of a cancer could suppress the ability of the tumour to metastasize, but the cancer could retain its other neoplastic features. Third, tumours could reverse back to the state they were in when that particular oncogene first became activated. The inactivation of an oncogene that first initiated autonomous cellular proliferation could cause a tumour to regain dependence on external growth signals. Once a tumour is incapable of proliferating — even though it might have acquired genetic alterations that contribute towards its ability to be immortal, induce angiogenesis or invade through stromal barriers — these other neoplastic characteristics would become effectively silenced, as the tumour would be unable to expand in number. Fourth, tumour cells could regain normal physiological programmes and undergo cellcycle arrest, cellular differentiation and/or apoptosis. If the tumour cells undergo differentiation, they might lose — through epigenetic mechanisms — the gene-expression programmes that contributed vital characteristics for a neoplasia.

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PERSPECTIVES Tumour regression is stereotypically associated with proliferative arrest, differentiation and/or apoptosis1–8. Tumour cells often seem to be almost completely eliminated, although this has yet to be rigorously addressed. In other models, some of the tumour cells persist as differentiated cells that function normally3. In several cases, tumour regression is associated with a loss of angiogenesis, which might contribute to the loss of tumour mass1,4,5. However, the loss of neoplastic features also occurs via cellautonomous mechanisms, because the inactivation of oncogenes in vitro can also result in a loss of neoplastic characteristics2,3. As a general rule, the inactivation of an oncogene that initiated tumorigenesis seems to be capable of inducing immediate, pronounced and frequently sustained tumour regression.

Table 1 | Oncogene inactivation induces tumour regression in mouse models Oncogene

Cancer

Results of oncogene inactivation

MYC

Lymphoma, leukaemia Osteogenic sarcoma Breast adenocarcinoma Skin papilloma Islet-cell adenocarcinoma

Arrest, differentiation, apoptosis Arrest, differentiation Apoptosis? Arrest, differentiation? Arrest, differentiation, apoptosis

2 3 7 4 5

RAS

Melanoma Lung adenocarcinoma

Apoptosis Apoptosis

1 8

ABL

Lymphoma

Apoptosis

6

Fifth, tumours could indirectly lose their neoplastic features by no longer providing the cues to the normal tissue in the host to provide a supportive environment. For example, tumour cells might lose the capacity to elicit angiogenesis effectively, thereby restricting the capacity for further proliferative expansion. These mechanisms are not necessarily mutually exclusive. Most oncogenes are likely to contribute to tumorigenesis through many mechanisms. The mechanisms by which a particular oncogene contributes to tumorigenesis in a given tumour is likely to be variable and to depend on the type of cancer and the other genetic events that are associated with that tumour. Until recently, it was simply not possible to experimentally address the consequences of the inactivation of an oncogene in a naturally arising tumour. Observed. The development of strategies to conditionally regulate oncogenes in transgenic mouse models has made it possible to examine the effects of oncogene inactivation (BOX 1). Most investigators have chosen the tetracycline regulatory system (Tet System)12,13, which

References

allows oncogene transcription to be regulated by doxycycline. In this manner, it has been shown that the inactivation of an oncogene (for example, MYC, ABL and RAS) can result in sustained tumour regression in several different types of tumour (for example, lymphoma, leukaemia, bone and lung)1–3,6–8 (TABLE 1). Use of an alternative and complementary strategy — the tamoxifen system — has similarly shown that neoplastic features of pancreatic islet-cell tumours and skin papillomas reverse following oncogene inactivation4,5. Collectively, these results provide a compelling demonstration that, at least in experimental animal models, the inactivation of a single oncogene can be sufficient to reverse the neoplastic process. The consequences of inactivating different oncogenes in different cancer types are surprisingly similar. In all of the cases examined so far, tumour regression is very rapid — complete regression of the tumours is generally observed within a few days1–8. Tumours transplanted into new syngeneic mice also had a conditional neoplastic phenotype that could be suppressed by oncogene inactivation2,3.

Genetically complex tumours regress

Human cancers are genetically complex. The observation that oncogene inactivation can induce tumour regression in these animal models would not be relevant to our understanding of human neoplasia if these tumours were caused by a single event. However, several observations indicate that this is unlikely — at least in some of the tumour models. First, the latency of tumour onset is often more than 10 weeks1–8, which would be unlikely if a single oncogene was sufficient. In most of these transgenic models, the oncogene was induced throughout embryogenesis, indicating that during this time and the subsequent weeks after birth, but before tumour onset, other mutations accumulate. Second, the tumours tend to

g Loss of cues to stromal cells

A

A+B

A+B+C

A+B+C ?

a No effect, e Differentiation

partial effect

d Arrest

f Apoptosis

b Loss of some neoplastic features c Complete reversion Figure 1 | Possible outcomes following oncogene inactivation. Tumorigenesis occurs as a result of genetic changes in oncogenes and/or tumoursuppressor genes, in this case in A, B and C. But what is the effect of inactivating the product of just one oncogene, such as A? a | There could be no effect. b | There could be loss of some of the neoplastic features that were contributed by these oncogenes. c | There could be complete reversal of the neoplastic state, as the tumour cells revert to the state that the cells were in before the oncogene was activated. Physiological programmes might resume, resulting in d | arrest, e | differentiation or f | apoptosis. g | Finally, there could be a loss of cues to normal stromal cells and the ability of cells to continue proliferative expansion might be limited — for example, by the inability to induce angiogenesis. These different possibilities are not mutually exclusive and the consequences for a given oncogene might depend on the type of cancer and the other genetic events in the particular tumour.

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PERSPECTIVES occur sporadically within the tissue of origin, indicating that only rare cells become tumorigenic, despite diffuse expression of the oncogene as a transgene1–8. Third, the primary tumours can be accompanied by metastasis, which probably reflects the acquisition of additional genetic events in tumour cells3. At least under these circumstances, cancer was probably the consequence of several independent events. In addition, two strategies have been used to address whether more genomically complex tumours can undergo tumour regression following oncogene inactivation. Investigators generated melanomas or lung cancers in which more than one genetic event was involved — for example, oncogene activation in combination with the absence of a particular tumour suppressor (for example, Ink4a and Arf, and p53) — and, in these, the inactivation of a single oncogene was still sufficient to induce the regression of tumours1,8. Similarly, in pancreatic islet-cell tumours caused by MYC and BCL-XL, the inactivation of MYC alone was sufficient to induce tumour regression5. In addition, we have directly examined the MYC-induced lymphomas generated in our model system for their genomic complexity. We were able to analyse the chromosomal changes in these lymphomas by spectral karyotypic analysis (SKY) — a technique in which each chromosome can be identified in a metaphase spread by using a unique fluorescent label — and show that even genomically complex and unstable tumours are capable of undergoing sustained regression following the inactivation of a single oncogene14. Potential caveats

The experiments performed in animal models provide compelling evidence that tumorigenesis can be reversed by inactivating a single oncogene. However, there are many caveats to these experimental observations. So far, only a few oncogenes have been examined. Not surprisingly, investigators have focused on the particularly potent oncogenes that are most commonly associated with human neoplasia. Perhaps these oncogenes are more likely to induce reversible tumorigenesis because they contribute to the maintenance of neoplastic features in many ways. In addition, in all the cases examined so far, oncogenes were inactivated in tumours in which the oncogene was necessarily the initiating tumorigenic event. Oncogene inactivation might be less effective at inducing tumour regression if its activation was a late event during malignant progression.

Box 1 | Mouse models of oncogene inactivation

Tet system a | In these transgenic mice, oncogene expression is regulated by the tetracycline transactivating protein (tTA), which is expressed in a particular tissue according to the promoter that regulates it. tTA is also regulated by doxycycline (Dox). In the absence of doxycycline, tTA forms an active dimer that can drive expression of the oncogene from the seven tetO sequence. In the presence of doxycycline, tTA undergoes a conformational change and is unable to bind to the seven tetO sequence to activate transcription.

Tamoxifen system b | These transgenic mice are engineered so that a chimeric gene product is produced between an oncogene and the oestradiol receptor (ERT). The activity of this product is post-transcriptionally regulated with 4-hydroxytamoxifen (4-OHT). In the absence of 4-OHT, the oncoprotein–ERT fusion is sequestered by heat-shock proteins (HSPs). Addition of 4-OHT results in release of the oncoprotein–ERT fusion.

a tTA system Promoter

b Tamoxifen system tTA

Promoter

pA

Oncogene–ERT pA

HSP Dox tTA

tTA

+ Dox

(Active)

Dox tTA

tTA

(Inactive)

Oncoprotein–ERT (Inactive) HSP

+ 4-OHT 4-OHT Oncoprotein–ERT (Active)

tTA

tTA

7 x tetO

TATA

Oncogene pA

Oncoprotein

A neoplastic state has not always been found to be reversible following oncogene inactivation — tumours can become independent of the oncogene that initiated tumorigenesis1–3,5,7. The neoplastic changes that are induced by overexpressing the large T antigen in the salivary gland can become independent of it15, and perhaps this is an example of an oncogene that induces tumorigenesis indirectly, by inducing genomic destabilization. In this regard, we previously reported that even brief MYC activation can induce tumorigenesis in immortal rodent cell lines16. Interestingly, MYC-induced lymphomas that became resistant to regression — caused by switching off MYC with doxycycline — no longer expressed either the human MYC transgene, or the endogenous c-Myc, Nmyc or Lmyc, confirming that, in this model system, tumours can become independent of an initiating oncogenic event14. We found that each lymphoma had


a reproducible tendency to escape the requirement of MYC overexpression to sustain their neoplastic phenotype, but we have yet to define what determines whether tumours relapse after oncogene inactivation. The consequences of the inactivation of an oncogene will therefore probably vary depending on the genetic features of a particular type of cancer2. Additionally, genetic events might occur that can functionally replace a given oncogene. We have observed that haematopoietic tumours that had relapsed after MYC inactivation, showed novel clonal chromosomal translocations, indicating that the mechanism by which tumours relapse is through the acquisition of a new mutant gene product that might phenocopy the ability of MYC to sustain tumorigenesis14. We infer that these genomic events result in the disruption of gene products that functionally substitute for the requirement of MYC to maintain a neoplastic phenotype.

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PERSPECTIVES Furthermore, the ability of the inactivation of a single oncogene to induce sustained regression is likely to be influenced by many factors, such as the type of tumour and the context of other genetic events. One example to illustrate this point is that the ability of breast cancer cells to escape dependence on the MYC or Wnt1 oncogenes is greatly facilitated in tumours that had acquired activation of RAS or loss of p53 function, respectively7,17. In general, the consequences of oncogene inactivation are likely to depend on the specific oncogene that initiated tumorigenesis in a given tumour, the array of genetic events in a given tumour and the epigenetic factors — all of which contribute to the phenotypic characteristics of a particular type of cancer. It will be very important to identify the context in which oncogene inactivation will induce sustained tumour regression. The most important caveat is that all of these experiments were performed in mice. Observations in mice might not translate to humans for several reasons. First, in animal experiments, the tumours were necessarily initiated by the marked overexpression of a particular oncogene. Oncogenes are not always overexpressed in human tumours, so their inactivation might have less effect. Second, tumours arising in transgenic mice might not be as genomically complex as human tumours, which are caused by many events. Fixing one broken gene product might therefore not be as effective. Third, animal models sometimes give rise to tumours that do not have the phenotypic characteristics that are typical of human tumours. In particular, they have not always been shown to be metastatic1,4–8. Yet, metastasis is responsible for the morbidity and mortality that are associated with human cancer. These differences could compromise our ability to extrapolate these findings in animal models to the development of therapeutic treatments for humans with cancer. Reversing human tumorigenesis

Despite the many potential problems with the results obtained using animal models, there is, reassuringly, substantial evidence that the inactivation of oncogenes in human tumours can also result in tumour regression9,10. The most compelling example is provided by the treatment of human patients who have chronic myelogenous leukaemia (CML), with the ABL kinase inhibitor, imatinib (Glivec), as it can induce sustained clinical remission18–20. Imatinib is also effective in the treatment of gastrointestinal-associated stromal tumours (GISTs)21.

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The experience with imatinib will not necessarily be applicable to other types of cancer. CML is a myeloproliferative disorder that is probably caused by just one oncogene, so it is perhaps not surprising that the inactivation of BCR–ABL has a clinical effect. Notably, imatinib is not as clinically effective after CML has progressed from the CML phase to a blast crisis, with the appearance of an acute myeloid leukaemia20. Even when drugs are effective, human tumours can frequently escape dependence on a particular oncogene. A case point is the frequently observed resistance to imatinib, which seems to be mediated by mutations in BCR–ABL that prevent the ability of imatinib to bind to the oncoprotein22,23. Nevertheless, there seems to be cause for increased optimism that drugs that target oncogenes will be effective in the treatment of some human cancers. To develop effective treatments for human cancer, we will need to know when, for a given cancer, the inactivation of a specific oncogene will be effective. The most effective treatments will require the inactivation of many oncogenes. What seems to be most required at this time is an understanding of why oncogene inactivation ever causes tumour regression. Brief oncogene inactivation

We might recently have gained insight into why oncogene inactivation induces tumour regression, while we were attempting to address a more pragmatic question. We were concerned that even if it were possible to develop a panel of drugs to inactivate each oncogene, two problems would remain. First, normal proto-oncogene functions are generally essential, so efforts to constitutively inactivate an oncogene would probably be toxic to normal cells. Second, the cessation of oncogene inactivation would probably result in the reemergence of the tumour. Quite surprisingly, we found that this is not necessarily the case, as even brief inactivation of an oncogene can result in the loss of a neoplastic phenotype 3. To examine the duration of oncogene inactivation that is required to reverse a neoplastic phenotype, we used a transgenic model of MYC-induced osteogenic sarcoma. First, we showed that following inactivation of the MYC oncogene, immature osteogenic tumours differentiated into mature osteocytes. Then, we asked what happens if we reactivate MYC. To our surprise, the now-differentiated tumour cells were refractory to MYC reactivation for the resurrection of their neoplastic phenotype. Instead, MYC reactivation induced apoptosis. We concluded that there are circumstances in which the brief inactivation of an oncogene could


be sufficient to induce sustained loss of a neoplastic phenotype. Our results suggested to us a new perspective on how oncogenes sustain tumorigenesis and an explanation for why oncogene inactivation can result in tumour regression. Cancer does not seem to be simply a summation of genetic events that occur in a cell that serves as a passive vehicle for malignant transformation. Instead, the consequences of the activation of an oncogene such as MYC seem to be highly dependent on the particular differentiative state of a cell. There seem to be particular differentiative windows that provide the appropriate epigenetic context that is permissive for certain genetic events to promote and sustain tumorigenesis, as has been suggested previously24. Even briefly interrupting oncogene activation can be sufficient to change this differentiative context, thereby permanently revoking the ability of that oncogene to be capable of sustaining tumorigenesis. This hypothesis was anticipated by studies that were first described two decades ago25,26. A temperature-sensitive SRC mutant was introduced into chick muscle cells and was found to induce their transformation at the permissive temperature. Shifting the cells to the non-permissive temperature resulted in their differentiation, but reactivation of SRC by shifting the cells back to the permissive temperature now resulted in cell death. The relative permissiveness or barrier to the ability of an oncogene to sustain tumorigenesis seems to be largely determined by epigenetic factors. However, it is important to interpret our findings cautiously, until it is determined if they apply to other oncogenes and cancer types. A model

We therefore propose a possible unifying model that could account for why, in at least some experimental systems, oncogene inactivation causes widespread phenotypic changes in cellular proliferation, differentiation, angiogenesis and apoptosis. The consequences of oncogene inactivation might be mediated by epigenetic changes in patterns of gene expression that occur as tumour cells enter a differentiative state (FIG. 2). In a permissive differentiative state, oncogene activation induces and sustains a neoplastic phenotype. Following oncogene inactivation, differentiation occurs and the resulting change in the epigenetic programme results in the loss of neoplastic features. Under these circumstances, tumour cells proliferatively arrest, lose the capacity to induce angiogenesis and restore the capacity to undergo apoptosis. Then, if the oncogene becomes reactivated in this non-permissive



PERSPECTIVES a Neoplasia

Epigenetic programme: cellular proliferation

Therapeutic implications Cell cycle

b Normal

Apoptosis

? Cell cycle

c Apoptosis

Differentiation

Apoptosis

MYC off/on

Differentiative state: non-permissive Epigenetic programme: apoptosis

Differentiation

MYC off

Differentiative state: non-permissive Epigenetic programme: differentiation

generally result in the loss of a neoplastic phenotype.

MYC on

Differentiative state: permissive

Cell cycle

Differentiation

Apoptosis

Figure 2 | Oncogene inactivation might revoke tumorigenesis by changing the epigenetic programme of a cell. a | MYC activation in a permissive differentiative context activates cell-cycle transit and blocks differentiation, but does not induce apoptosis. b | MYC inactivation results in the arrest of the cell cycle and the differentiation, and in some cases apoptosis, of tumour cells. c | MYC reactivation in this new mature differentiative context fails to induce cell-cycle transit, but instead induces apoptosis. The consequences of the inactivation and reactivation of an oncogene vary depending on the oncogene and the type of cancer. This model predicts that there are two complimentary ways in which tumorigenesis can be revoked: first, by targeting the inactivation of important oncogenes; or second, by changing the differentiative state.

differentiative state, the tumour cells fail to proliferate and, instead, can undergo apoptosis. Many observations support the notion that epigenetic, as well as genetic, events contribute to tumorigenesis. First, cancers frequently show changes in the expression of genes that are responsible for cell-cycle checkpoints, induction of angiogenesis, cellular adhesion, blocks in apoptosis and increased invasion and metastasis, and in some cases this occurs through epigenetic, as opposed to genetic, mechanisms27–31. Moreover, many of the most potent oncogenes (such as MYC, BCR–ABL and PML–RARα) might directly interact with gene products that regulate DNA modification and chromatin structure to modulate gene expression27,32–34. In particular, MYC activation has been suggested to contribute to tumorigenesis by inducing an angiogenic switch and changes in cell adhesion5,35. Finally, agents that can promote the differentiation of tumour cells in some cases result in tumour regression31,36,37. One of the most notable examples is the use of retinoic acid for the treatment of acute promyelocytic leukaemia36,37. Many of the essential features that are associated with tumorigenesis occur through epigenetic mechanisms.

Cancer is perhaps best appreciated as not just a collection of genetic events, but rather as specific genetic events that occur in requisite differentiative contexts24. Permitting differentiation of tumour cells can result in a loss of their neoplastic properties. Something that, perhaps, was not previously anticipated is that the inactivation of genetic events can revoke this permissive differentiative context by causing differentiation of tumour cells and a change in the epigenetic programme of cells. From this hypothesis, several testable predictions can be made. First, the patterns of gene expression induced by an oncogene will be different in cells that are permissive versus not permissive for tumorigenesis. In a permissive context, oncogene activation should be associated with the induction of genes associated with proliferation, immortalization, angiogenesis and metastatic invasion. Second, the ability of an oncogene to induce tumorigenesis should change with the age of the host and other states that influence the associated changes in the relative abundance of specific differentiative compartments. Third, drugs, metabolites or cytokines that can bypass the ability of an oncogene to block the differentiation of tumours will


By conceiving of cancer as genetic events that drive a permissive epigenetic programme, at least a partial explanation could potentially be offered for several enigmas that confound cancer biology. First, oncogenes are typically associated with specific types of cancer. This might reflect that tumours of a particular cell type provide the correct epigenetic context that allows an oncogene to induce cancer. Second, malignant progression seems to occur because of genetic events that arise in a particular order. The order in which genetic events are acquired in tumours could, in part, matter because only particular oncogenes would be capable of initiating tumour progression in a particular differentiative context. Third, the kinds of cancer that occur most commonly in neonatal, young and adult hosts differ, and, in general, tumours correspond to the malignant expansion of immature cells. In both cases, this could occur because of the relative abundance of particular differentiative subsets of cellular lineages that can allow a given oncogene to induce tumorigenesis. Fourth, growth factors and cytokines that induce cellular activation or proliferation in normal cells can induce cell-cycle arrest or apoptosis in tumour cells. Perhaps, these factors — by restoring physiological programmes — change the differentiative status and epigenetic context, so, in this new state, oncogenes induce cell-cycle arrest or apoptosis. The most important implication of our model is that it might be possible to treat some cancers by only briefly or intermittently inactivating an oncogene. So far, inhibitors of oncogenes have been continuously administered, but our results indicate that perhaps it could be as effective, if not more effective, to intermittently inactivate an oncogene. In addition, our results indicate that there might be two broad approaches by which it should be possible to treat cancer (FIG. 2). First, the targeted inactivation of specific oncogenes should result in the loss of a neoplastic phenotype when tumour cells are able to resume their physiological programme. Second, the modulation of the differentiative context of tumour cells might be effective in revoking the ability of oncogenes to sustain a neoplastic phenotype by changing the epigenetic programme. Either the genetic events or epigenetic programme of a tumour cell can be targeted, but in either case the consequence can be to revoke tumorigenesis. In summary, oncogene inactivation has been shown to induce tumour regression in animal models and in human patients. Even

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PERSPECTIVES brief oncogene inactivation might be sufficient to induce sustained loss of a neoplastic phenotype under some circumstances. Tumours can escape the dependence on oncogenes, apparently by acquiring new genetic events. Collectively, these results indicate that cancer is caused by genetic events that occur in a requisite epigenetic context. So, cancer might be treatable by inactivating oncogenes or by inducing the differentiation of tumours. The current challenge is to define when oncogenes will be good therapeutic targets and define how specific differentiative states provide the permissive epigenetic contexts to support neoplasia. By understanding how genetic events sustain tumorigenesis in specific epigenetic contexts, we might be able to treat cancer through the development of drugs that inactivate oncogenes or revoke permissive epigenetic states that are responsible for tumorigenesis. Dean W. Felsher is at the Division of Oncology, Departments of Medicine and Pathology, Stanford University, 269 Campus Drive, CCSR 1105, Stanford, California 94305-5151, USA. e-mail: [email protected] doi:10.1038/nrc1070 1. 2.

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15.

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17.

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Acknowledgements Thank you to the members of my laboratory for a critical reading of the manuscript, and to H. Varmus and G. Klein for kindly bringing relevant literature to my attention. D.W.F. is supported by grants from the National Institutes of Health, the Lymphoma Research Foundation, the Elsa Pardee Foundation and the Esther Ehrman Lazard Faculty Scholar Award.

Online links DATABASES The following terms in this article are linked online to: Cancer.gov: http://www.cancer.gov/cancer_information/ bone cancer | chronic myelogenous leukaemia | leukaemia | lung cancer LocusLink: http://www.ncbi.nih.gov/LocusLink/ ABL | BCL-XL | BCR | CDKN2A | ERT | LMYC | MYC | NMYC | p53 | PML | RARα | RAS | SRC | Wnt1 FURTHER INFORMATION Dean Felsher’s lab: http://www-med.stanford.edu/felsherlab/ Access to this interactive links box is free online.

