p53 modulation as a therapeutic strategy in gastrointestinal stromal tumors.

The KIT-inhibitor imatinib mesylate (IM) has greatly improved the treatment of metastatic gastrointestinal stromal tumors (GIST). IM exhibits strong antiproliferative effects but fails to induce sufficient levels of apoptosis resulting in low pathologic complete remission rates and a high rate of se...

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Autores principales:	Joern Henze, Thomas Mühlenberg, Susanne Simon, Florian Grabellus, Brian Rubin, Georg Taeger, Martin Schuler, Juergen Treckmann, Maria Debiec-Rychter, Takahiro Taguchi, Jonathan A Fletcher, Sebastian Bauer
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/eb08851ab2234325acf4d31cce831a44
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spelling	oai:doaj.org-article:eb08851ab2234325acf4d31cce831a442021-11-18T07:17:17Zp53 modulation as a therapeutic strategy in gastrointestinal stromal tumors.1932-620310.1371/journal.pone.0037776https://doaj.org/article/eb08851ab2234325acf4d31cce831a442012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22662219/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The KIT-inhibitor imatinib mesylate (IM) has greatly improved the treatment of metastatic gastrointestinal stromal tumors (GIST). IM exhibits strong antiproliferative effects but fails to induce sufficient levels of apoptosis resulting in low pathologic complete remission rates and a high rate of secondary progression in the metastatic setting. Upregulation of p53 by MDM2 inhibitors has been shown to induce apoptosis in p53 wildtype tumors. Analyzing a series of 62 mostly untreated, localized and metastatic GIST we detected a low rate (3%) of inactivating p53 mutations, thus providing a rationale for further exploration of p53-directed therapeutic strategies. To this end, we studied nutlin-3, an inhibitor of the p53 antagonist MDM2, and RITA, a putative p53 activator, in GIST cell lines. Nutlin-3 effectively induced p53 at therapeutically relevant levels, which resulted in moderate antiproliferative effects and cell cycle arrest in p53 wildtype GIST cell lines GIST430, GIST48 and GIST48B. P53 reactivation substantially improved the apoptotic response after effective KIT inhibition with sunitinib and 17-AAG in IM-resistant cell lines. The commonly used imatinib-sensitive cell lines GIST882 and GIST-T1 were shown to harbor defective p53 and therefore failed to respond to nutlin-3 treatment. RITA induced p53 in GIST48B, followed by antiproliferative effects and a strong induction of apoptosis. Surprisingly, GIST-T1 was also highly sensitive to RITA despite lacking functional p53. This suggested a more complex, p53-independent mechanism of action for the latter compound. No antagonistic effects from p53-activating drugs were seen with any drug combination. Our data provide first evidence that modulation of the MDM2/p53 pathway may be therapeutically useful to improve the apoptotic response of KIT-inhibitory drugs in the treatment of naïve GIST, with p53 mutation status being a predictive factor of response.Joern HenzeThomas MühlenbergSusanne SimonFlorian GrabellusBrian RubinGeorg TaegerMartin SchulerJuergen TreckmannMaria Debiec-RychterTakahiro TaguchiJonathan A FletcherSebastian BauerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 5, p e37776 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Joern Henze Thomas Mühlenberg Susanne Simon Florian Grabellus Brian Rubin Georg Taeger Martin Schuler Juergen Treckmann Maria Debiec-Rychter Takahiro Taguchi Jonathan A Fletcher Sebastian Bauer p53 modulation as a therapeutic strategy in gastrointestinal stromal tumors.
description	The KIT-inhibitor imatinib mesylate (IM) has greatly improved the treatment of metastatic gastrointestinal stromal tumors (GIST). IM exhibits strong antiproliferative effects but fails to induce sufficient levels of apoptosis resulting in low pathologic complete remission rates and a high rate of secondary progression in the metastatic setting. Upregulation of p53 by MDM2 inhibitors has been shown to induce apoptosis in p53 wildtype tumors. Analyzing a series of 62 mostly untreated, localized and metastatic GIST we detected a low rate (3%) of inactivating p53 mutations, thus providing a rationale for further exploration of p53-directed therapeutic strategies. To this end, we studied nutlin-3, an inhibitor of the p53 antagonist MDM2, and RITA, a putative p53 activator, in GIST cell lines. Nutlin-3 effectively induced p53 at therapeutically relevant levels, which resulted in moderate antiproliferative effects and cell cycle arrest in p53 wildtype GIST cell lines GIST430, GIST48 and GIST48B. P53 reactivation substantially improved the apoptotic response after effective KIT inhibition with sunitinib and 17-AAG in IM-resistant cell lines. The commonly used imatinib-sensitive cell lines GIST882 and GIST-T1 were shown to harbor defective p53 and therefore failed to respond to nutlin-3 treatment. RITA induced p53 in GIST48B, followed by antiproliferative effects and a strong induction of apoptosis. Surprisingly, GIST-T1 was also highly sensitive to RITA despite lacking functional p53. This suggested a more complex, p53-independent mechanism of action for the latter compound. No antagonistic effects from p53-activating drugs were seen with any drug combination. Our data provide first evidence that modulation of the MDM2/p53 pathway may be therapeutically useful to improve the apoptotic response of KIT-inhibitory drugs in the treatment of naïve GIST, with p53 mutation status being a predictive factor of response.
format	article
author	Joern Henze Thomas Mühlenberg Susanne Simon Florian Grabellus Brian Rubin Georg Taeger Martin Schuler Juergen Treckmann Maria Debiec-Rychter Takahiro Taguchi Jonathan A Fletcher Sebastian Bauer
author_facet	Joern Henze Thomas Mühlenberg Susanne Simon Florian Grabellus Brian Rubin Georg Taeger Martin Schuler Juergen Treckmann Maria Debiec-Rychter Takahiro Taguchi Jonathan A Fletcher Sebastian Bauer
author_sort	Joern Henze
title	p53 modulation as a therapeutic strategy in gastrointestinal stromal tumors.
title_short	p53 modulation as a therapeutic strategy in gastrointestinal stromal tumors.
title_full	p53 modulation as a therapeutic strategy in gastrointestinal stromal tumors.
title_fullStr	p53 modulation as a therapeutic strategy in gastrointestinal stromal tumors.
title_full_unstemmed	p53 modulation as a therapeutic strategy in gastrointestinal stromal tumors.
title_sort	p53 modulation as a therapeutic strategy in gastrointestinal stromal tumors.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/eb08851ab2234325acf4d31cce831a44
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p53 modulation as a therapeutic strategy in gastrointestinal stromal tumors.

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