Usually, oncogenes are involved in tumor development and increase the possibility that the development of a cell directs towards cancer. First of all, that the concept of oncogene addiction, although intriguing, may have limited relevance for the majority of tumors. The use of molecular targeted agents in combination with cytotoxic agents, and the advances in systems biology and network theory as a means to. The efficacy of this strategy requires novel methods, including integrative genomics and systems biology, to. Thyroid carcinoma tc is the most common malignancy of endocrine organs with an increasing incidence in industrialized countries. The majority of tc are characterized by a good prognosis, even though cases with aggressive forms not cured by standard therapies are also present. Erbb family members represent important biomarkers and drug targets for modern precision therapy. Request pdf oncogene addiction tumors induced in conditional oncomice can show remarkable different responses to subsequent oncogene deprivation. 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. 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. With knowledge gained through clinical trials, the oncogene addiction model was revised 71. 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. They develop a sirtuin inhibitor that mimics sirt3 depletion and kills dlbcl cells.
Cigarette smoke enhances oncogene addiction to cmet and desensitizes egfrexpressing nonsmall cell lung cancer to egfr tkis chihyen tu1,2,3, fangju cheng4, chuanmu chen1, shuling wang5, yuchun hsiao6. 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. Elledge1, 1howard hughes medical institute, department of genetics, harvard medical school, department of medicine, division of genetics, brigham and womens hospital, boston, ma 02115, usa correspondence. They have gained considerable importance as paradigms for oncoprotein addiction and personalized medicine. In pugilistic parlance, the onetwo punch is a devastating combination of blows, with the first punch setting the stage and the second delivering the knockout. A prime clinical example of oncogene addiction is in cml. In some cases, oncogene inactivation results in the elimination of all or almost all tumor cells through apoptosis by the phenomenon described as oncogene addiction. Oncogene addiction as a foundational rationale for. The achilles heel of cancer oncogene addiction cancer a. Although a number of oncogenes and tumor suppressors, such as pi3k, ras, p53, pten. 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, sharma and settleman, 2007. The use of selective epidermal growth factor receptor egfr kinase inhibitors in lung cancer treatment represents yet another example of oncogene addiction that. It is now an axiom in oncology that human cancers often evolve through a multistage process that extends over decades. Ron kinase transphosphorylation sustains met oncogene addiction.
Any of a family of genes that normally encodes proteins that are involved in cell growth or regulation e. 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. This phenomenon, called oncogene addiction, applies to all those settings in which cancer cells appear to be dependent on a single overactive oncogene for. 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. The erbb2her2 oncogene is amplified in 25%30% of breast cancers berger et al. Bim, puma, and the achilles heel of oncogene addiction.
Oncogene addiction of mouse tumors predicts the outcome of therapeutic. In retrospect, the first evidence of oncogene addiction can be drawn from. 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. Interplay between hsf1 and p53 signaling pathways in cancer. Oncogene addiction describes the dependence of some cancers on one or a few. While in vitro and in vivo examples abound documenting the. This phenomenon has been defined nononcogene addiction noa.
This is the concept of oncogene addiction, the elucidation of which has led to substantial progress in therapeutic interventions. We propose that addiction may be an illusion generated as a consequence of. Proietti, florent dingli d, damarys loew d, elmer a. Moreover, target therapies have led to low rates of partial response and prompted the emergence of resistance. Identified oncongenes include ras, originally noted in bladder tumors, and p53. Being a feature of tumor cells, targeting noa can represent a point of intervention for. Oncogene addiction an overview sciencedirect topics. Khan academy offers practice exercises, instructional videos, and a personalized learning dashboard that empower learners to study at. In its simplest embodiment, oncogene addiction refers to the curious observation that a tumor cell, despite its plethora of genetic alterations, can seemingly exhibit. Oncogene addiction as a foundational rationale for targeted anti.
Combinations of the methods described in the preceding sections have been used to address several important questions in cancer biology, including oncogene addiction and the cooperation and interdependence of various oncogenes and tumor suppressors. This phenomenon, called oncogene addiction, provides a rationale for molecular targeted therapy. Despite this complexity, their growth and survival can often be impaired by the inactivation of a single oncogene. 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. Known and novel roles of the met oncogene in cancer. Tumor dormancy and oncogene addiction felsher 2008. The term oncogene addiction was first coined by bernard weinstein to describe the dependency of certain tumor cells on a single activated oncogenic protein or pathway to maintain their malignant properties, despite the likely accumulation of multiple gain and lossoffunction mutations that contribute to tumorigenicity. Oncogene is one of the worlds leading cancer journals. However, because resistance mechanisms often emerge. To describe this addiction of cancer cells to the functions of. Oncogene addiction may also contribute to the clinical success of agents that target the erbb family receptor, erbb2her2.
Oncogene addiction a driver of tumorigenesis, but also a predictor of treatment response to alk. An oncogene is a modified gene, or a series of nucleotides that encode a protein, and direct the cell to the development of a neoplastic phenotype. Wed like to understand how you use our websites in order to improve them. This definition was first introduced by bernard weinstein in 2000, with particular reference to the observation that some cyclin doverexpressing cancers reverse their malignant phenotype upon cyclind depletion by means of rna interference rnai. The p53 protein, which is primarily activated in response to. In experimental transgenic mouse models the consequences of oncogene inactivation depend upon the genetic and cellular context. Cancer cells contain multiple genetic and epigenetic abnormalities. However, after prolonged inactivation of myc in a conditional transgenic mouse model of e. Pdf a view on egfrtargeted therapies from the oncogene.
The term oncogene addiction is a hallmark of cancer, meaning that cancers are primarily driven by divergent signaling pathways of oncogenes. They activate important signaling pathways triggering adaptive mechanisms that maintain cellular homeostasis. An oncogene is a gene that has the potential to cause cancer. Dec 02, 20 the term oncogene addiction was coined in 2000 by bernard weinstein, m. 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. This phenomenon, called oncogene addiction, applies to all those settings in which cancer cells appear to be dependent on a single overactive oncogene for their proliferation and survival 99,100. Multistage carcinogenesis and the concept of oncogene addiction. Clinical responses to oncogene inhibitors result from direct effects on cellintrinsic growth signals and disruption of downstream messages that produce a protumor immunosuppressive microenvironment.
Cancers free fulltext targeting nononcogene addiction. Mar 26, 20 cancer cells undergo extensive genetic and epigenetic rewiring to support the malignant phenotype, and yet cell survival and proliferation often remain dependent on one or a limited number of driver mutations. Winslow, tyler jacks, in the molecular basis of cancer fourth edition, 2015. Jun 10, 2019 the p53 and hsf1 transcription factors are key players in cellular responses to stress. Oncogene definition of oncogene by medical dictionary. Dna damage, drug development, oncogene addiction, targeted. Oncogene addiction as a foundational rationale for targeted. Online pdf converter convert files to and from pdfs for free. Addiction to oncogenesthe achilles heal of cancer science. Oncogene and nononcogene addiction ji luo,1 nicole l. While in vitro and in vivo examples abound documenting the existence of this phenomenon, the mechanistic underpinnings that govern oncogene addiction are just beginning. Nononcogene addiction and the stress phenotype of cancer. A view on egfrtargeted therapies from the oncogeneaddiction perspective article pdf available in frontiers in pharmacology 4.
Addiction to oncogenes the achilles heal of cancer. Receptors for the scatter factors hgf and msp that are encoded by the met and ron oncogenes are key players in invasive growth. A view on egfrtargeted therapies from the oncogeneaddiction. Secondly, that the nature of oncogene activation, i.
Blockade of stat3 oncogene addiction induces cellular. A single cancer cell frequently contains mutations in multiple genes, gross chromosomal abnormalities, and widespread changes in its gene expression profile hn11. By this rationale, cancer cells are addicted to both oncogenes and non oncogenes. Oncogene addiction and tumor mutational burden in non. Sirt3 depletion induces dlbcl cell death by reducing glutamine flux to the tca cycle and acetylcoa pools. The compelling concept proposed to account for these evidences is known as oncogene addiction. Oncogene addictiona rationale for molecular targeting. This is because the proteins encoded by these genes often have multiple roles in. Hsf1 is a transcription factor that is activated by a variety of proteindenaturing cellular stresses including heat and hypoxia. In this issue, lindquist and her colleagues illustrate an example of non oncogene addiction by uncovering a surprising and critical role of heatshock factor 1 hsf1 in tumorigenesis dai et al. What is thought to underlie the phenomenon of oncogene addiction is the observation that. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Amplification of the met oncogene results in kinase activation, deregulated expression of an invasive growth phenotype, and addiction to met oncogene signaling i. Hsf1 is mainly activated by proteotoxic stress, and its induction leads to the synthesis of chaperones that provide proteome integrity.
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