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Oncogene addiction: resetting the safety switch?
| Content Provider | Semantic Scholar |
|---|---|
| Author | Li, Yulin Choi, Peter S. Felsher, Dean W. |
| Copyright Year | 2014 |
| Abstract | The term " oncogene addiction " was first coined by Dr. Bernard Weinstein to describe the exquisite dependency of tumor cells on the expression of specific oncogenes for their relentless proliferation and survival [1]. Since cancers generally have accumulated multiple genetic and epigenetic abnormalities, it is surprising that they can remain dependent on any particular oncogenic driver. This " Achilles' heel " of cancer has been widely exploited by targeted therapy of many human cancers, such as imatinib for BCR-ABL-driven leukemia, crizotinib for leukemia with FLT3-ITD mutations, gefitinib for lung adenocarcinoma with EGFR mutations, and vemurafenib for melanomas with B-RAF mutations. However, the mechanism of oncogene addiction is not clear. Several non-mutually exclusive mechanisms for oncogene addiction have been proposed, such as synthetic lethality, genetic streamlining, oncogenic shock, and the safety switch model. In the synthetic lethality model, some mutations that develop during cancer evolution are either neutral or adaptive only in the presence of the driver oncogene [2]. However, these same mutations are deleterious to the cancer cells in the absence of the driver oncogene, rendering the cancer cells unfit for survival. In the genetic streamlining model, the cancer cells are rewired by the dominant oncogenic driver and lose the cellular functions that are not essential for survival and proliferation [3]. Thus, the tumors will collapse once the dominant signaling pathway upon which cancer cells are highly dependent is suppressed. The oncogenic shock model posits that there is a differential decay of the pro-survival and pro-apoptotic signals upon the inactivation of an oncogene. This differential decay results in a vulnerable window, causing the cell to irreversibly undergo apoptosis [4]. Previously, we also proposed the cellular safety switch model. We suggested that the inactivation of the driver oncogene restores the normal cellular safety switch, and thus leads to proliferative arrest, apoptosis, and/or cellular senescence [5, 6]. However, a molecular mechanism has not been elucidated for any of these models. Now we have uncovered the molecular mechanism underlying the cellular safety switch model in MYC-induced tumors [7]. MYC inactivation is associated with the loss of many of the hallmark features of tumorigenesis and results in proliferative arrest, apoptosis, differentiation, and senescence, as well as the shutdown of angiogenesis. These phenotypes induced by MYC inactivation are surprisingly similar to those resulting from the loss in function of miR-17-92, a MYC target gene known to regulate multiple aspects of tumorigenesis, such as proliferation, … |
| Starting Page | 7986 |
| Ending Page | 7987 |
| Page Count | 2 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&op=download&page=article&path%5B%5D=2474&path%5B%5D=4520 |
| PubMed reference number | 25275297v1 |
| Volume Number | 5 |
| Journal | Oncotarget |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Addictive Behavior Adenocarcinoma of lung (disorder) Apoptosis Carcinogenesis Cell Aging Congenital Abnormality Fusion Proteins, bcr-abl MIR17 wt Allele Malignant Neoplasms Mutation Oncogenes Phenotype Proliferative vitreoretinopathy Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-myb Proto-Oncogene Proteins c-myc Shock Vemurafenib abl Oncogene cancer cell crizotinib emotional dependency gefitinib imatinib leukemia melanoma study of epigenetics |
| Content Type | Text |
| Resource Type | Article |
