Elimination of extrachromosomally amplified MYC genes from human tumor cells reduces their tumorigenicity.

Hoff, Daniel D. Von; McGill, J.; Forseth, B; Davidson, Karen; Bradley, Thomas; Devanter, D R Van; Wahl, Geoffrey M.

doi:10.1073/pnas.89.17.8165

Cited by 154 publications

(84 citation statements)

References 30 publications

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“…1F). However, our data suggest that EGFR TKI resistance may not be mediated entirely by selection for a subpopulation of tumor cells lacking extrachromosomal EGFRvIII DNA but may also involve rapid single-step elimination, as has been described for loss of the DHFR gene on double minutes in the absence of methotrexate (26, 27) and the loss of MYCC or MYCN from double minutes in the presence of hydroxyurea (28). These independent and complementary mechanisms of EGFRvIII regulation, coupled to intercellular signaling between EGFRvIII High /EGFRvIII Low tumor cells (6), enable GBMs to achieve an EGFRvIII High /EGFRvIII Low ratio that is optimal for growth and survival, including in response to EGFR TKI therapy.…”

supporting

confidence: 49%

Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA

Nathanson

Gini

Mottahedeh³

et al. 2014

Science

520

552

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Intratumoral heterogeneity contributes to cancer drug resistance, but the underlying mechanisms are not understood. Single-cell analyses of patient-derived models and clinical samples from glioblastoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from extrachromosomal DNA. After drug withdrawal, reemergence of clonal EGFR mutations on extrachromosomal DNA follows. These results indicate a highly specific, dynamic, and adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA.

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supporting

confidence: 49%

Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA

Nathanson

Gini

Mottahedeh³

et al. 2014

Science

520

552

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“…Moreover, the demonstration that experimental suppression of amplified MYC genes from human tumour cells is associated with loss of tumorigenicity [28]suggests its involvement in tumour aggressiveness. Although amplification or enhanced expression of C-MYC have been detected in several tumours, including sarcomas [3, 25, 29, 30, 31], the significance of C-MYC over…”

Section: Discussionmentioning

confidence: 99%

Prognostic Significance of Nuclear Accumulation of c-myc and mdm2 Proteins in Synovial Sarcoma of the Extremities

et al. 2000

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We retrospectively analysed a group of primary tumours from 32 patients with synovial sarcomas of the extremities by using immunohistochemistry on paraffin-embedded tissue samples in order to investigate the prognostic significance of the nuclear accumulation of c-myc and mdm2 proteins. Nuclear positive immunostaining for c-myc or mdm2 proteins were revealed in 9/32 cases (28%) and in 6/30 cases (20%), respectively. Since c-myc protein appears to be a key factor for keeping cells in an active proliferative stage, we also analysed the growth compartment of each tumour by using the MIB1 monoclonal antibody, specific for Ki-67 antigen. A high MIB1 index was found in 8/31 cases (26%) but was not associated either with c-myc or mdm2 nuclear positivity. Analysis of clinical outcome was performed in a subgroup of 27 patients with a minimum follow-up of 24 months. Among the clinicopathologic parameters and the biological markers, only the nuclear accumulation of c-myc was significantly associated with a higher relapse rate (p = 0.03). Accordingly, survival analysis confirmed a trend toward a poor event-free survival rate and a worse outcome in c-myc-positive cases (p = 0.12). These data demonstrate that assessment of c-myc nuclear accumulation can be useful to identify high-risk subsets of patients with synovial sarcoma of the extremities.

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“…Examples of genes amplified on DMs include MYCN in neuroblastoma [12], C-MYC in colon cancer cells [13], EGFR in gliomas [14], and eIF-5A2 in ovarian cancer cells [15], and all of which when lost via DMs contributes to reversal of the cancer phenotype [12], [13], [14], [16]. Elimination of amplifications of oncogenes on DMs has also been shown to induce apoptotic cell death, cellular differentiation, and cellular senescence [13], [17], [18].…”

Section: Introductionmentioning

confidence: 99%

“…The loss of DMs has been demonstrated in many cancer cell lines [12], [13], [17], [19], [20], [21], [22]. Non-lethal low concentrations of hydroxyurea (HU) has first been found to increase the loss of DMs from mouse cells containing amplified DHFR [23], and was later found to have the same effect in mammalian cancer cells [13], [24]. The loss of DMs by low concentrations of HU can increase drug sensitivity [24] and reduce tumorigenicity of cancer cell lines [13].…”

Section: Introductionmentioning

confidence: 99%

“…Non-lethal low concentrations of hydroxyurea (HU) has first been found to increase the loss of DMs from mouse cells containing amplified DHFR [23], and was later found to have the same effect in mammalian cancer cells [13], [24]. The loss of DMs by low concentrations of HU can increase drug sensitivity [24] and reduce tumorigenicity of cancer cell lines [13]. Most importantly, the loss of DMs was contributed to their entrapment into micronuclei (MN) [13] and this entrapment can also be enhanced by low concentrations of HU [25], [26].…”

Section: Introductionmentioning

confidence: 99%

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Gemcitabine Eliminates Double Minute Chromosomes from Human Ovarian Cancer Cells

Zhao

Quan

et al. 2013

PLoS ONE

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Double minute chromosomes are cytogenetic manifestations of gene amplification frequently seen in cancer cells. Genes amplified on double minute chromosomes include oncogenes and multi-drug resistant genes. These genes encode proteins which contribute to cancer formation, cancer progression, and development of resistance to drugs used in cancer treatment. Elimination of double minute chromosomes, and therefore genes amplified on them, is an effective way to decrease the malignancy of cancer cells. We investigated the effectiveness of a cancer drug, gemcitabine, on the loss of double minute chromosomes from the ovarian cancer cell line UACC-1598. Gemcitabine is able to decrease the number of double minute chromosomes in cells at a 7500X lower concentration than the commonly used cancer drug hydroxyurea. Amplified genes present on the double minute chromosomes are decreased at the DNA level upon gemcitabine treatment. Gemcitabine, even at a low nanomolar concentration, is able to cause DNA damage. The selective incorporation of double minutes chromatin and γ-H2AX signals into micronuclei provides a strong link between DNA damage and the loss of double minute chromosomes from gemcitabine treated cells. Cells treated with gemcitabine also showed decreased cell growth, colony formation, and invasion. Together, our results suggest that gemcitabine is effective in decreasing double minute chromosomes and this affects the biology of ovarian cancer cells.

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Elimination of extrachromosomally amplified MYC genes from human tumor cells reduces their tumorigenicity.

Cited by 154 publications

References 30 publications

Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA

Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA

Prognostic Significance of Nuclear Accumulation of c-myc and mdm2 Proteins in Synovial Sarcoma of the Extremities

Gemcitabine Eliminates Double Minute Chromosomes from Human Ovarian Cancer Cells

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