Imatinib targeting of KIT-mutant oncoprotein in melanoma

Xiaofeng Jiang, Jun Zhou, Noah K. Yuen, Christopher Corless, Michael Heinrich, Jonathan A. Fletcher, George D. Demetri, Hans R. Widlund, David E. Fisher, F. Stephen Hodi

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

Purpose: Melanoma subtypes based on anatomic location and UV light exposure can be further classified based on genetic alterations recently identified. Mutations and gene amplification in KIT have been described in a significant percentage of mucosal and acral melanomas. We recently reported a patient with metastatic mucosal melanoma harboring a known KIT mutation treated with imatinib mesylate who experienced a major response. Biological effects of KIT inhibition in these melanomas remain poorly understood. We sought to investigate further the effects of imatinib in these melanoma subsets. Experimental Design: Mucosal melanoma cells were analyzed for KIT aberrations by genomic sequencing, quantitative PCR, and single nucleotide polymorphism analyses. Imatinib effects were assayed by viability measurements and apoptotic cytotoxicity. Tumor cell lysates were assayed by Western blots to determine effects on multiple signaling pathways after imatinib exposure. Results: Mucosal melanoma cells exhibited imatinib sensitivity correlating with KIT mutational status. Imatinib dramatically decreased proliferation and was cytotoxic to a KIT mutated and amplified cell culture. Exposure to drug affected the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT, JAK-STAT, and antiapoptotic pathways. Conclusions: Rational targeting of KIT in melanoma offers a unique and potent clinical opportunity. In vitro analyses revealed major sensitivity to KIT kinase inhibition by imatinib, with potent induction of melanoma cell apoptosis. Biochemical studies identified changes in signaling molecules regulating proliferation and survival responses, which may serve as mediators and/or biomarkers of in vivo treatment efficacy. Pathways affected by KIT inhibition provide a model for understanding components in effective melanoma cell death and insights into targeting for resistance mechanisms.

Original languageEnglish (US)
Pages (from-to)7726-7732
Number of pages7
JournalClinical Cancer Research
Volume14
Issue number23
DOIs
StatePublished - Dec 1 2008

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Oncogene Proteins
Melanoma
Imatinib Mesylate
Phosphatidylinositol 3-Kinase
Mutation
Gene Amplification
Ultraviolet Rays
Mitogen-Activated Protein Kinases
Single Nucleotide Polymorphism
Cell Death
Research Design
Phosphotransferases
Extremities
Cell Culture Techniques
Biomarkers
Western Blotting
Apoptosis
Polymerase Chain Reaction
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Imatinib targeting of KIT-mutant oncoprotein in melanoma. / Jiang, Xiaofeng; Zhou, Jun; Yuen, Noah K.; Corless, Christopher; Heinrich, Michael; Fletcher, Jonathan A.; Demetri, George D.; Widlund, Hans R.; Fisher, David E.; Hodi, F. Stephen.

In: Clinical Cancer Research, Vol. 14, No. 23, 01.12.2008, p. 7726-7732.

Research output: Contribution to journalArticle

Jiang, X, Zhou, J, Yuen, NK, Corless, C, Heinrich, M, Fletcher, JA, Demetri, GD, Widlund, HR, Fisher, DE & Hodi, FS 2008, 'Imatinib targeting of KIT-mutant oncoprotein in melanoma', Clinical Cancer Research, vol. 14, no. 23, pp. 7726-7732. https://doi.org/10.1158/1078-0432.CCR-08-1144
Jiang, Xiaofeng ; Zhou, Jun ; Yuen, Noah K. ; Corless, Christopher ; Heinrich, Michael ; Fletcher, Jonathan A. ; Demetri, George D. ; Widlund, Hans R. ; Fisher, David E. ; Hodi, F. Stephen. / Imatinib targeting of KIT-mutant oncoprotein in melanoma. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 23. pp. 7726-7732.
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