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Identifying the determinants of response to MDM2 inhibition.

Saiki AY, Caenepeel S, Cosgrove E, Su C, Boedigheimer M, Oliner JD - Oncotarget (2015)

Bottom Line: To better understand the nature of these exceptions, we screened a panel of 260 cell lines and noted similar discrepancies.To facilitate clinical testing of this hypothesis, we identified a rationally derived copy number cutoff for assignment of functionally relevant MDM2 amplification.Applying this cutoff resulted in a pan-cancer MDM2 amplification rate far lower than previously published.

View Article: PubMed Central - PubMed

Affiliation: Oncology Research, Amgen, Inc., Thousand Oaks, California, USA.

ABSTRACT
Previous reports have provided evidence that p53 mutation is a strong negative predictor of response to MDM2 inhibitors. However, this correlation is not absolute, as many p53Mutant cell lines have been reported to respond to MDM2 inhibition, while many p53WT cell lines have been shown not to respond. To better understand the nature of these exceptions, we screened a panel of 260 cell lines and noted similar discrepancies. However, upon extensive curation of this panel, these apparent exceptions could be eliminated, revealing a perfect correlation between p53 mutational status and MDM2 inhibitor responsiveness. It has been suggested that the MDM2-amplified subset of p53WT tumors might be particularly sensitive to MDM2 inhibition. To facilitate clinical testing of this hypothesis, we identified a rationally derived copy number cutoff for assignment of functionally relevant MDM2 amplification. Applying this cutoff resulted in a pan-cancer MDM2 amplification rate far lower than previously published.

No MeSH data available.


Related in: MedlinePlus

Sensitivity to MDM2 inhibition highly correlates with TP53 mutational status(A) The sensitivity to AMGMDS3 was profiled across a panel of 260 tumor cell lines in a 72-hour cell proliferation assay. The TP53 mutational status of each cell line was annotated according to the data available in COSMIC (v44 release), http://www.sanger.ac.uk/cosmic [11, 28]. Similar representations of previously published nutlin-3a sensitivity data from (B) Garnett et al. [8] and (C) Barretina et al. [9] have been shown for comparison. The highest concentration of nutlin-3a tested by Garnett et al. and Barretina et al. was 8 μM.
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Figure 1: Sensitivity to MDM2 inhibition highly correlates with TP53 mutational status(A) The sensitivity to AMGMDS3 was profiled across a panel of 260 tumor cell lines in a 72-hour cell proliferation assay. The TP53 mutational status of each cell line was annotated according to the data available in COSMIC (v44 release), http://www.sanger.ac.uk/cosmic [11, 28]. Similar representations of previously published nutlin-3a sensitivity data from (B) Garnett et al. [8] and (C) Barretina et al. [9] have been shown for comparison. The highest concentration of nutlin-3a tested by Garnett et al. and Barretina et al. was 8 μM.

Mentions: As a first step towards identifying the determinants of sensitivity to MDM2 inhibition, a panel of 260 human tumor cell lines of diverse tissue origins was screened in a 72-hour cell proliferation assay. The effect of MDM2 inhibitor AMGMDS3 (Figure S1) on cell proliferation was determined by relative cell count as measured by nuclear staining, with IC50 values ranging from 0.01 μM to > 50 μM (Figure 1A, Table S1). In agreement with previous findings (plotted from published data in Figure 1B–1C; [8, 9]), sensitivity to MDM2 inhibition was highly correlated with p53 mutational status. This was a predictable result, as p53 mutations prevent p53 from activating transcriptional targets responsible for inducing cell cycle arrest and apoptosis. However, the correlation between p53 mutational status and sensitivity was not universal: some p53Mutant cell lines appeared to be sensitive to MDM2 inhibition, while some p53WT cell lines appeared to be insensitive. We suspected that some of these discrepancies might be related to misannotation or other confounding factors, and we therefore set out to comprehensively curate this cell line panel.


Identifying the determinants of response to MDM2 inhibition.

Saiki AY, Caenepeel S, Cosgrove E, Su C, Boedigheimer M, Oliner JD - Oncotarget (2015)

Sensitivity to MDM2 inhibition highly correlates with TP53 mutational status(A) The sensitivity to AMGMDS3 was profiled across a panel of 260 tumor cell lines in a 72-hour cell proliferation assay. The TP53 mutational status of each cell line was annotated according to the data available in COSMIC (v44 release), http://www.sanger.ac.uk/cosmic [11, 28]. Similar representations of previously published nutlin-3a sensitivity data from (B) Garnett et al. [8] and (C) Barretina et al. [9] have been shown for comparison. The highest concentration of nutlin-3a tested by Garnett et al. and Barretina et al. was 8 μM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480710&req=5

Figure 1: Sensitivity to MDM2 inhibition highly correlates with TP53 mutational status(A) The sensitivity to AMGMDS3 was profiled across a panel of 260 tumor cell lines in a 72-hour cell proliferation assay. The TP53 mutational status of each cell line was annotated according to the data available in COSMIC (v44 release), http://www.sanger.ac.uk/cosmic [11, 28]. Similar representations of previously published nutlin-3a sensitivity data from (B) Garnett et al. [8] and (C) Barretina et al. [9] have been shown for comparison. The highest concentration of nutlin-3a tested by Garnett et al. and Barretina et al. was 8 μM.
Mentions: As a first step towards identifying the determinants of sensitivity to MDM2 inhibition, a panel of 260 human tumor cell lines of diverse tissue origins was screened in a 72-hour cell proliferation assay. The effect of MDM2 inhibitor AMGMDS3 (Figure S1) on cell proliferation was determined by relative cell count as measured by nuclear staining, with IC50 values ranging from 0.01 μM to > 50 μM (Figure 1A, Table S1). In agreement with previous findings (plotted from published data in Figure 1B–1C; [8, 9]), sensitivity to MDM2 inhibition was highly correlated with p53 mutational status. This was a predictable result, as p53 mutations prevent p53 from activating transcriptional targets responsible for inducing cell cycle arrest and apoptosis. However, the correlation between p53 mutational status and sensitivity was not universal: some p53Mutant cell lines appeared to be sensitive to MDM2 inhibition, while some p53WT cell lines appeared to be insensitive. We suspected that some of these discrepancies might be related to misannotation or other confounding factors, and we therefore set out to comprehensively curate this cell line panel.

Bottom Line: To better understand the nature of these exceptions, we screened a panel of 260 cell lines and noted similar discrepancies.To facilitate clinical testing of this hypothesis, we identified a rationally derived copy number cutoff for assignment of functionally relevant MDM2 amplification.Applying this cutoff resulted in a pan-cancer MDM2 amplification rate far lower than previously published.

View Article: PubMed Central - PubMed

Affiliation: Oncology Research, Amgen, Inc., Thousand Oaks, California, USA.

ABSTRACT
Previous reports have provided evidence that p53 mutation is a strong negative predictor of response to MDM2 inhibitors. However, this correlation is not absolute, as many p53Mutant cell lines have been reported to respond to MDM2 inhibition, while many p53WT cell lines have been shown not to respond. To better understand the nature of these exceptions, we screened a panel of 260 cell lines and noted similar discrepancies. However, upon extensive curation of this panel, these apparent exceptions could be eliminated, revealing a perfect correlation between p53 mutational status and MDM2 inhibitor responsiveness. It has been suggested that the MDM2-amplified subset of p53WT tumors might be particularly sensitive to MDM2 inhibition. To facilitate clinical testing of this hypothesis, we identified a rationally derived copy number cutoff for assignment of functionally relevant MDM2 amplification. Applying this cutoff resulted in a pan-cancer MDM2 amplification rate far lower than previously published.

No MeSH data available.


Related in: MedlinePlus