Mechanisms of Disease: oncogene addiction—a rationale for molecular targeting in cancer therapy

Weinstein, I. Bernard; Joe, Andrew K.

doi:10.1038/ncponc0558

Cited by 637 publications

(456 citation statements)

References 64 publications

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“…This might partially explain why cancer cells need much higher levels of Plk1 for proliferation. In this regard, Plk1 may be an enzyme to which cancer cells have become 'addicted' in a manner proposed by Weinstein and Joe (2006). Our data suggest that Plk1 depletion can lead to checkpoint activation not only in G2/M, as in MCF10A clone 12, but also in S phase, as in the hTERT-RPE1 clones.…”

Section: Plk1 Depletion Activates Checkpointsupporting

confidence: 54%

Plk1 depletion in nontransformed diploid cells activates the DNA-damage checkpoint

Lei

Erikson

2008

Oncogene

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We previously reported that polo-like kinase 1 (Plk1) depletion by lentivirus-based RNA interference led to mitotic arrest and apoptosis in cancer cells, whereas normal diploid cell lines, hTERT-RPE1 and MCF10A, survived a similar level of depletion. To study homogeneous cell lines, we generated several Plk1-depleted hTERT-RPE1 and MCF10A clones that were derived from single cells depleted of Plk1. We found that in the long term, Plk1 depletion slowed proliferation of hTERT-RPE1 cells, apparently due to attenuated progression through S phase. These cells had altered morphology and were elongated compared with control. In contrast, MCF10A clones with mild levels of depletion showed no obvious phenotype. They appeared to have normal proliferation rates with no cell-cycle arrest. However, one MCF10A clone, which was severely depleted of Plk1, although viable, showed sporadic G2/M arrest and apoptosis. This MCF10A clone and all the hTERT-RPE1 clones displayed evidence of DNA-damage checkpoint activation. These data further support the interpretation that cancer cell lines have a much greater requirement for Plk1 than normal nontransformed diploid cells.

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Section: Plk1 Depletion Activates Checkpointsupporting

confidence: 54%

Plk1 depletion in nontransformed diploid cells activates the DNA-damage checkpoint

Lei

Erikson

2008

Oncogene

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“…The 'oncogene addiction' theory suggests a tumour will have unyielding dependence on a particular perturbation of a single gene [28]. The reality is that cancer cells are unstable and have many alterations [29].…”

Section: Introductionmentioning

confidence: 99%

The cell cycle and cancer

Williams

Stoeber

2011

The Journal of Pathology

565

406

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Deregulation of the cell cycle underlies the aberrant cell proliferation that characterizes cancer and loss of cell cycle checkpoint control promotes genetic instability. During the past two decades, cancer genetics has shown that hyperactivating mutations in growth signalling networks, coupled to loss of function of tumour suppressor proteins, drives oncogenic proliferation. Gene expression profiling of these complex and redundant mitogenic pathways to identify prognostic and predictive signatures and their therapeutic targeting has, however, proved challenging. The cell cycle machinery, which acts as an integration point for information transduced through upstream signalling networks, represents an alternative target for diagnostic and therapeutic interventions. Analysis of the DNA replication initiation machinery and mitotic engine proteins in human tissues is now leading to the identification of novel biomarkers for cancer detection and prognostication, and is providing target validation for cell cycle-directed therapies.

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“…Recently, a third theme has been investigated and emerged as possible target in cancer therapy. Dr. Bernard Weinstein was the first to propose that even though cancer cells contain multiple mutations, the cell is dependent on one or only a few genes for the maintenance of their phenotype [86][87][88][89]. The hypothesis of 'oncogene addiction' refers to the "Achilles' heel" of cancer cells, explaining the observation that a tumor cell can exhibit dependence on a single oncogenic pathway or protein for its sustained proliferation and survival, despite its diversity of genetic alterations.…”

Section: Addictions Of Cancer Cells Oncogene Addiction and Tumor Suppmentioning

confidence: 99%

“…The validity of the oncogene addiction hypothesis is based on numerous experiments in genetically engineered mouse models and observations in patients, whereby the reversal of one or a few of the abnormal mutations in genes profoundly inhibited the growth of the cancer cells or even lead to the improvement of survival rates [88]. Inactivation of oncogenes can be achieved by various experimental methods, including RNA interference, inducible gene expression systems, small-molecule inhibitors, antibodies and dominant-negative interference [91].…”

Section: Addictions Of Cancer Cells Oncogene Addiction and Tumor Suppmentioning

confidence: 99%

Cancer stem cells and addicted cancer cells

Logtenberg¹,

Boonstra²

2013

Oncol Discov

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Advanced tumors represent a genetically heterogeneous population of cells, which compromise subpopulations with distinct properties. Research indicates that a specific population of cells within the heterogeneous population contain stem cell-like properties. These 'cancer stem cells' are much like normal stem cells and have the capacity to self-renew, sustain the entire cancerous tissues and provide a reservoir of cells for recurrence after therapy and drug resistance. Cancer stem cells can arise from normal, adult stem cells, from progenitor cells or from fully matured cell types. They are likely generated by the process of epithelial-mesenchymal transition, through which differentiated cells acquire stem-cell like properties. This process potentially underlies the mechanism by which metastases evolve. Furthermore, mutations may render cancer cells dependent on the activity of one or more specific signaling pathways in the cell. This phenomenon is termed 'oncogene addiction' and represents the Achilles' heel of the cancer cell. As the concept of oncogene addiction in tumor cells proves to be very complex, additional models have been proposed to account for the variations in pathway dependencies and their intricate interactions. The combined knowledge concerning cancer stem cells, oncogene addiction and drug therapy resistance may lead to the identification of new avenues to improved drug strategies that address tumor heterogeneity and mechanisms of escape.

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Mechanisms of Disease: oncogene addiction—a rationale for molecular targeting in cancer therapy

Cited by 637 publications

References 64 publications

Plk1 depletion in nontransformed diploid cells activates the DNA-damage checkpoint

Plk1 depletion in nontransformed diploid cells activates the DNA-damage checkpoint

The cell cycle and cancer

Cancer stem cells and addicted cancer cells

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