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Imatinib Targeting of KIT-Mutant Oncoprotein in Melanoma

Authors' Affiliations: ¹ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; ² Department of Pathology, Brigham and Women's Hospital, Harvard Medical School; ³ Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Cutaneous Biology Research Center, Department of Dermatology, Melanoma Program, Massachusetts General Hospital, Harvard Medical School; ⁴ Melanoma Program and ⁵ Ludwig Center, Dana-Farber Cancer Institute, Boston, Massachusetts; ⁶ John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii; and ⁷ Department of Pathology and ⁸ Division of Hematology and Oncology, Oregon Health & Science University and Portland VA Medical Center, Portland, Oregon

Requests for reprints: F. Stephen Hodi, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115. Phone: 617-632-5053; Fax: 617-582-7992; E-mail: stephen_hodi{at}dfci.harvard.edu.

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.

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