Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy

Pishas, Kathleen I.; Neuhaus, Susan J.; Clayer, Mark; Adwal, Alaknanda; Brown, Michael P.; Evdokiou, Andreas; Callen, David F.; Neilsen, Paul M.

doi:10.3892/or.2013.2454

Cited by 3 publications

(2 citation statements)

References 33 publications

(37 reference statements)

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“…HDM2 antagonist has augmented the apoptotic response to drozitumab in vitro in a panel of sarcoma cell lines and ex vivo human sarcoma patients. The scientists have postulated that the key factor that contributes to the synergistic effects between these molecules is upregulation of DR5 receptor expression following the p53 activation [94]. However, the development of drozitumab has been discontinued in 2010 [208].…”

Section: Drug Combinations For the Supporting Of Anti-cancer Activmentioning

confidence: 99%

Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists

Kocik

Machula

Wiśniewska

et al. 2019

Cancers

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The protein p53, known as the “Guardian of the Genome”, plays an important role in maintaining DNA integrity, providing protection against cancer-promoting mutations. Dysfunction of p53 is observed in almost every cancer, with 50% of cases bearing loss-of-function mutations/deletions in the TP53 gene. In the remaining 50% of cases the overexpression of HDM2 (mouse double minute 2, human homolog) protein, which is a natural inhibitor of p53, is the most common way of keeping p53 inactive. Disruption of HDM2-p53 interaction with the use of HDM2 antagonists leads to the release of p53 and expression of its target genes, engaged in the induction of cell cycle arrest, DNA repair, senescence, and apoptosis. The induction of apoptosis, however, is restricted to only a handful of p53wt cells, and, generally, cancer cells treated with HDM2 antagonists are not efficiently eliminated. For this reason, HDM2 antagonists were tested in combinations with multiple other therapeutics in a search for synergy that would enhance the cancer eradication. This manuscript aims at reviewing the recent progress in developing strategies of combined cancer treatment with the use of HDM2 antagonists.

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Section: Drug Combinations For the Supporting Of Anti-cancer Activmentioning

confidence: 99%

Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists

Kocik

Machula

Wiśniewska

et al. 2019

Cancers

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“…No patients received neoadjuvant chemotherapy or radiotherapy within 1 year before tissue collection. Patients 6, 11, and 14 were previously described in Pishas and colleagues (13).…”

Section: Clinical Materialsmentioning

confidence: 99%

Nutlin-3a Efficacy in Sarcoma Predicted by Transcriptomic and Epigenetic Profiling

et al. 2014

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Nutlin-3a is a small-molecule antagonist of p53/MDM2 that is being explored as a treatment for sarcoma. In this study, we examined the molecular mechanisms underlying the sensitivity of sarcomas to Nutlin-3a. In an ex vivo tissue explant system, we found that TP53 pathway alterations (TP53 status, MDM2/MDM4 genomic amplification/mRNA overexpression, MDM2 SNP309, and TP53 SNP72) did not confer apoptotic or cytostatic responses in sarcoma tissue biopsies (n ¼ 24). Unexpectedly, MDM2 status did not predict Nutlin-3a sensitivity. RNA sequencing revealed that the global transcriptomic profiles of these sarcomas provided a more robust prediction of apoptotic responses to Nutlin-3a. Expression profiling revealed a subset of TP53 target genes that were transactivated specifically in sarcomas that were highly sensitive to Nutlin-3a. Of these target genes, the GADD45A promoter region was shown to be hypermethylated in 82% of wild-type TP53 sarcomas that did not respond to Nutlin-3a, thereby providing mechanistic insight into the innate ability of sarcomas to resist apoptotic death following Nutlin-3a treatment. Collectively, our findings argue that the existing benchmark biomarker for MDM2 antagonist efficacy (MDM2 amplification) should not be used to predict outcome but rather global gene expression profiles and epigenetic status of sarcomas dictate their sensitivity to p53/MDM2 antagonists. Cancer Res; 74(3); 921-31. Ó2013 AACR.

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Overcoming Cancer Cell Resistance to Death Receptor Targeted Therapies

Twomey

Hallett

Zhang

2015

Resistance to Targeted Anti-Cancer Therapeutics

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Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy

Cited by 3 publications

References 33 publications

Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists

Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists

Nutlin-3a Efficacy in Sarcoma Predicted by Transcriptomic and Epigenetic Profiling

Overcoming Cancer Cell Resistance to Death Receptor Targeted Therapies

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