Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity.

Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity. Research Abstract Details 

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Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity. Abstract Text:

Ellen Weisberg,Renee D Wright,Jingrui Jiang,Arghya Ray,Daisy Moreno,Paul W Manley,Doriano Fabbro,Elizabeth Hall-Meyers,Laurie Catley,Klaus Podar,Andrew L Kung,James D Griffin,

BACKGROUND & AIMS: Activating mutations in platelet-derived growth factor receptor alpha (PDGFRA) have been reported in a subset of gastrointestinal stromal tumor (GIST) patients who do not express the mutant stem cell factor receptor c-kit. The responsiveness of mutant PDGFRA-positive GIST to imatinib depends on the location of the PDGFRA mutation; for example, the V561D juxtamembrane domain mutation is more sensitive to imatinib than the D842V kinase domain mutation. In this study, we compare the effects of 3 tyrosine kinase inhibitors, PKC412 and nilotinib, and imatinib, on 2 GIST-related PDGFRA mutants, V561D and D842V, which possess differential sensitivity to imatinib. METHODS: The effects of PKC412, nilotinib, and imatinib, alone and in combination, were evaluated via in vitro proliferation studies performed with V561D- or D842V-PDGFRA mutants. The effects of nilotinib and PKC412, alone and combined, were investigated in vivo. RESULTS: PKC412 potently inhibited the V561D-PDGFRA mutant in vitro and the D842V-PDGFRA mutant in vitro and in vivo. Both imatinib and nilotinib displayed potent activity in vitro against the V561D-PDGFRA mutant but were significantly less efficacious against D842V-PDGFRA. However, when combined with either imatinib or PKC412, nilotinib showed no evidence for antagonism and acted in a cooperative fashion against D842V-PDGFRA. CONCLUSIONS: Our findings support the clinical testing of PKC412 for treatment of mutant PDGFRA-GIST. The data also support the use of nilotinib as a treatment option for V561D-PDGFRA-associated GIST, although the reduced sensitivity of D842V-PDGFRA probably limits the potential of nilotinib monotherapy for D842V-PDGFRA-associated GIST.

Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity. Publishing Authors By Initials

E Weisberg,RD Wright,J Jiang,A Ray,D Moreno,PW Manley,D Fabbro,E Hall-Meyers,L Catley,K Podar,AL Kung,JD Griffin,

For similar xenograft model antitumor assays research abstracts see: xenograft model antitumor assays research

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Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Gastroenterology

VOLUME: 131

Page Numbers: 1734-42

Journal Abbreviation: Gastroenterology

ISSN: 0016-5085

DAY: 20

MONTH: 09

YEAR: 2006

Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 374630

Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity. Keywords Mesh Terms:

KEYWORDS: Xenograft Model Antitumor Assays

MESH TERMS: metabolism

Chemical & Substance for Abstract: Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity. Information

Substance Name: Receptor, Platelet-Derived Growth Factor

Registry Number: EC 2.7.1.112

Grant and Affiliation Information for Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity.

AFFILIATION: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA. Ellen_weisberg@dfci.harvard.edu

Country: United States

AGENCY: United States NIDDK

GRANT: DK50654

ACRONYM: DK

MEDLINETA: Gastroenterology

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