A proto oncogene is a normal gene that could become an oncogene due to mutations or increased expression. 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. These originate from a variety of settings, including human cancer cell lines, mouse tumor models, and clinical cancer studies table 1. Proto oncogenes code for proteins that help to regulate the cell growth and differentiation. Considering the large number of identified oncogenes and tumor suppressors, how does one determine what to target. However, rnai approaches suffer from significant offtarget effects that limit their utility. Pdf targeting ck2driven nononcogene addiction in b. A single cancer cell frequently contains mutations in multiple genes, gross chromosomal abnormalities, and widespread changes in its gene expression profile hn11. Bernard weinstein to describe the exquisite dependency of tumor cells on the expression of specific oncogenes for their relentless proliferation and survival. Oncogene addiction an overview sciencedirect topics. Despite its lethality, ibc remains poorly understood which has greatly limited its therapeutic management. Cancer is, an old adage goes, actually a hundred diseases masquerading as one. The paradigm of the met receptor tyrosine kinase eleonora orlando, daniel matthias aebersold. Epigenetic mechanisms of escape from braf oncogene.
However, after prolonged inactivation of myc in a conditional transgenic mouse model of e. Oncogeneaddicted cells constitutively express the amount of activated oncogene required for growth and proliferation. Erbb family members represent important biomarkers and drug targets for modern precision therapy. We have pioneered the development of genetic tools. However, the mechanisms explaining oncogene addiction remain elusive. Metastatic medullary thyroid cancer mtc is incurable and fdaapproved kinase inhibitors that include oncogenic ret as a target do not result in complete responses. The continued importance of maintaining or enhancing ret kinase activity to survive the cdk inhibitors also can be utilized for therapeutic synergy with ret kinase inhibition by targeting both transcriptional and signaling addiction to the oncogene. Transcriptional inhibition by cdk79 inhibitor sns032. Oncogene addiction describes the phenomenon by which some cancers that contain multiple genetic and epigenetic abnormalities remain dependent on addicted to one or a. Oncogene addiction is the dependence of a cancer cell on one overactive gene or pathway for the cells survival and growth.
Fourth, it evolves over time oncogene addiction tumor suppressor hypersensitivity multistage theory of carcinogenesis and other expressions were brand new to me and i. Oncogene addictiona rationale for molecular targeting. Transcriptional targeting of oncogene addiction in medullary thyroid cancer. The success of agents that target aberrantly expressed bone fide oncogenic receptor tyrosine kinases rtks, such as bcrabl in the case of cml or egfr in the case of diverse epithelial malignancies, rests on the presumption that transformed cells have become, in contrast to their normal. Cigarette smoke enhances oncogene addiction to cmet and desensitizes egfrexpressing nonsmall cell lung cancer to egfr tkis chihyen tu1,2,3, fangju cheng4. Despite great promise, however, mapktargeted therapies in brafmutant tumors are limited by the emergence of drug resistance. Neoplasia and cancer pathogenesis cetuximab combined with multitargeted sirna against hsp90, ubch5, and src circumvented oncogene addiction, transactivation, and acquired resistance as a result of egfr ubiquitination, and mutationsdeletions in the kinase domain of egfr in colorectal ca. Combining oncogene targeted and immunomodulatory therapies may result in synergistic effects, producing increased response rates and longer periods of tumor control than can be achieved with. Reversion of tumor hepatocytes to normal hepatocytes during. Rnai has been increasingly used to understand such oncogene addiction and validate new therapeutic targets. Oncogene addiction may also contribute to the clinical success of agents that target the erbb family receptor, erbb2her2. Jci insight transcriptional targeting of oncogene addiction. Intervention works on the premise that all cancer cells harbor the mutant or amplified oncogene and are dependent on the oncogenic signaling pathway for proliferation and survival.
It has also been suggested that oncogene addiction leads to activation of both survival and apoptotic pathways, but in viable tumor cells, the prosurvival signal outweighs the apoptotic signal 18. Targeting molecular addictions in cancer british journal of cancer. Aug 26, 2008 the clinical efficacy of selective kinase inhibitors suggests that some cancer cells may become dependent on a single oncogene for survival. Oncogene addiction is a common phenomenon in human cancers and hence provides an attractive target for cancer therapy. Clinical responses to oncogene inhibitors result from direct effects on cellintrinsic growth signals and disruption of downstream messages that produce a protumor immunosuppressive microenvironment. Association studies of human mtcs and murine models suggest that the cdkrb. The elevated activity of transcription of oncogenes is presumably to drive aspects of tumors. Plateletderived growth factor b pdgfb overexpression induces gliomas of different grades from murine embryonic neural progenitors.
Cetuximab combined with multitargeted sirna against. Nononcogene addiction and the stress phenotype of cancer. Myc inactivation elicits oncogene addiction through both. Jan 24, 2012 is oncogene addiction clinically significant. We propose that addiction may be an illusion generated as a consequence of. In our fight against this dreaded disease, casualties abound and successes are few and far between. Implications for targeted therapies directed to receptor tyrosine kinases1,2 vinochani pillay, layal allaf, alexander l. The targeted inactivation of oncogenes can be associated with tumor regression through the phenomenon of oncogene addiction. Indeed, oncogene inactivation can result in the elimination of all or almost all tumor cells by various mechanisms through the phenomena described as oncogene addiction. Oncogene addiction as a foundational rationale for targeted. Oncogene addiction of mouse tumors predicts the outcome of therapeutic blockade of oncogene expression or.
We thus decided to utilize an integrative functional genomic strategy to identify the achilles heel of ibc cells. Oncogene addiction refers to dependence of malignancy on a single molecular aberration that drives proliferation and agg. Adaptation to hypoxia versus oncogene addiction giulia cheloni,1,2 martina poteti,1,3 silvia bono,1,2 erico masala,4 nathalie m. Modeling oncogene addiction using rna interference pnas. Inflammatory breast cancer ibc is the most lethal form of breast cancers with a 5year survival rate of only 40 %.
Oncogene addiction as a foundation of targeted cancer. With knowledge gained through clinical trials, the oncogene addiction model was revised 71. Since cancers generally have accumulated multiple genetic and epigenetic abnormalities, it is surprising that they can remain dependent on any particular oncogenic driver. The repair of these mutant gene products may be expected to subvert this neoplastic behavior. In some rare tumour cell lines, the corrupted activity of.
Pdf oncogene addiction and nononcogene addiction in. Oncogene addiction is thought to be the basis of the success of the tyrosine kinase inhibitor imatinib for cml in which bcrabl is the oncogene and gastrointestinal stromal tumors in which kit is the oncogene. Targeting specific genes contributing to non oncogene addiction may provide an attractive strategy for therapeutic vulnerability in lymphomas independent of their genetics luo et al. The notions of oncogene addiction and resistance to targeted agents are inextricably intertwined.
We have pioneered the development of genetic tools as. Over the last decade, researchers have accumulated evidence for oncogene addiction, and they are now teasing out exactly how such addiction takes placeand how tumors might escape it. An axiom in cancer research is that the multistage process of tumor formation 12 is driven by progressive acquisition of activating mutations in dominant growthenhancing genes oncogenes hn23 and inactivating. When we and others first described that myc inactivation reversed tumorigenesis, our explanation was somewhat prosaic not because we did not have an idea of the possible mechanisms, of which we proposed several, but we were aware that, at the time, it was hard enough to be certain of the observation. Little is known about the drivers of liver organotropic metastasis in um. These acquired defects generate cancer cellspecific vulnerabilities that provide a window of opportunity for targeted cancer treatments. Mutated braf and subsequent hyperactivation of the mapk signaling pathway has motivated the use of mapktargeted therapies for these tumors.
Oncogene addiction is a phenomenon that the survival of cancer cells depends on an activated oncogene or inactivation of tumor suppressor gene, and is regarded as the achilles heel of the successful molecular targeted therapies in cancer. Nonetheless, resistance to targeted therapies is frequently observed and it arises through multiple mechanisms, including mutations in the target gene. Abstract oncogene addiction is the dependence seen in some types of cancer cells on the presence or activity of an oncogene. A prime clinical example of oncogene addiction is in cml. 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. Transcriptional targeting of oncogene addiction in medullary thyroid cancer anisley valenciaga, 1 motoyasu saji, 1 lianbo yu, 2 xiaoli zhang, 2 ceimoani bumrah, 3 ayse s. All of them take into account cellautonomous cancerspecific properties and are known as i genetic streamlining, ii oncogenic shock and iii synthetic lethality sl. Addiction to oncogenesthe achilles heal of cancer science. Surgeon generals report 1988 cigarettes and other forms of tobacco are addicting. Oncogene and non oncogene addiction ji luo,1 nicole l.
Essentially, three models have been put forward to elucidate the mechanisms of oncogene addiction at the molecular level. The phenomenon of oncogene addiction, irrespective of its mechanistic underpinnings, is widely recognized as a likely contributor to the impressive clinical activity that has recently been observed following treatment with socalled rationallytargeted agents. What is thought to underlie the phenomenon of oncogene addiction is the observation that oncogenes elicit strong, opposing prosurvival and proapoptotic signals in cancer cells that favor growth and survival, and the acute inhibition of oncogene function tilts this balance toward cell death downward, 2003. While most cancers harbor multiple oncogenic mutations, a wealth of preclinical and clinical data supports that many cancers are sensitive to. One of the most common oncogenic events in human cancer is the activation of the myc oncogene. Oncogene addiction, that is, the acquired dependence of a cancer cell on the activity of a single oncogenic gene product, has been the basis. Oncogene addiction as a foundation of targeted cancer therapy. Only a subset of metactivated pathways are required to sustain oncogene addiction by a. Pdf modeling oncogene addiction using rna interference. Nononcogene addiction and the stress phenotype of cancer cells. We 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 5, 6. Nononcogene addiction to sirt3 plays a critical role in.
Mar 07, 2020 oncogene addiction describes the phenomenon by which some cancers that contain multiple genetic and epigenetic abnormalities remain dependent on addicted to one or a few genes for both. Reversion of tumor hepatocytes to normal hepatocytes. Oncogenic addiction is the proposed mechanism by which a tumor cell becomes largely reliant on a single activated oncogene 16,17. Sep 21, 2007 although a supporting role for hsf1 in an oncogenic melodrama is attractive, a model for non oncogene addiction with potentially greater ramifications for cancer treatment would argue that cancer cells experience high levels of proteotoxic stress and rely upon stress response pathways for survival and proliferation. Oncogene addiction describes the curious acquired dependence of tumor cells on an activated oncogene for their survival andor proliferation, a phenomenon that has important implications for the success of targeted cancer therapies. Tumorigenesis is generally caused by genetic changes that activate oncogenes or inactivate tumor suppressor genes. Mar 10, 2017 oncogene addiction describes the phenomenon in which some cancers that contain multiple genetic, epigenetic, and chromosomal abnormalities remain dependent on addicted to one or a few genes for both maintenance of the malignant phenotype and cell survival. Lymphomas that recur after myc suppression continue to. Life of patients with uveal melanoma um is largely threatened by liver metastasis. This is because the proteins encoded by these genes often have multiple roles in. Targeting a non oncogene addiction to the atrchk1 axis for the treatment of small cell lung cancer. Nicotine is the drug in tobacco that causes addiction. For the first time, we formally demonstrated that pdgfbinduced neoplasms undergo progression from nontumorigenic. Oncogene addiction is the dependence of a cancer cell on one overactive gene or.
Mechanisms of oncogene addiction we 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 5. Comoglio, silvia giordano and livio trusolino abstract the met tyrosine kinase stimulates cell scattering, invasion, protection from apoptosis and angiogenesis, thereby acting as a powerful expedient for cancer dissemination. The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. Cancers free fulltext targeting nononcogene addiction. Pdf tumor progression and oncogene addiction in a pdgfb. In retrospect, the earliest evidence of oncogene addiction can be traced back to studies using human tumorderived cell lines. Modeling oncogene addiction using rna interference. Chronic myeloid leukaemia cml is driven by the bcr. The met tyrosine kinase is a cell surface receptor for hepatocyte growth factor hgf. In its original version, it postulated that cancer cells display either oncogene addiction i. Targeted inhibition of the oncogene shuts off this signaling and shifts the cells into a dynamic state leading to death. Targeting a nononcogene addiction to the atrchk1 axis. The erbb2her2 oncogene is amplified in 25%30% of breast cancers berger et al. Transcriptional targeting of oncogene addiction in.
Oncogene addiction and tumor suppressor gene hypersensitivity. They have gained considerable importance as paradigms for oncoprotein addiction and personalized medicine. Targeting specific genes contributing to nononcogene addiction may provide an attractive strategy for therapeutic. About eight percent of all human tumors including 50% of melanomas carry gainoffunction mutations in the braf oncogene. Model illustrating the relationship between oncogene addiction and oncogenic shock. However, the role of oncogene addiction in gliomas has not been elucidated systematically. Although a supporting role for hsf1 in an oncogenic melodrama is attractive, a model for non oncogene addiction with potentially greater ramifications for cancer treatment would argue that cancer cells experience high levels of proteotoxic stress and rely upon stress response pathways for survival and proliferation. Oncogeneaddicted cells can require just the right amount of signaling for survival. Oncogene addiction in chronic myeloid leukaemia jackson. Oncogene addiction as a foundational rationale for targeted anti. Feb, 2015 clinical evidence for oncogene addiction. Oct 18, 2011 the suppression of oncogenic levels of myc is sufficient to induce sustained tumor regression associated with proliferative arrest, differentiation, cellular senescence, andor apoptosis, a phenomenon known as oncogene addiction.
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