p53 Modulation as a Therapeutic Strategy in Gastrointestinal Stromal Tumors

DSpace/Manakin Repository

p53 Modulation as a Therapeutic Strategy in Gastrointestinal Stromal Tumors

Citable link to this page


Title: p53 Modulation as a Therapeutic Strategy in Gastrointestinal Stromal Tumors
Author: Henze, Joern; Mühlenberg, Thomas; Simon, Susanne; Grabellus, Florian; Rubin, Brian; Taeger, Georg; Schuler, Martin; Treckmann, Juergen; Debiec-Rychter, Maria; Taguchi, Takahiro; Bauer, Sebastian; Fletcher, Jonathan A.

Note: Order does not necessarily reflect citation order of authors.

Citation: Henze, Joern, Thomas Mühlenberg, Susanne Simon, Florian Grabellus, Brian Rubin, Georg Taeger, Martin Schuler, et al. 2012. p53 modulation as a therapeutic strategy in gastrointestinal stromal tumors. PLoS ONE 7(5): e37776.
Full Text & Related Files:
Abstract: 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.
Published Version: doi:10.1371/journal.pone.0037776
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360609/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10406320
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)


Search DASH

Advanced Search