title: Anti-KIT monoclonal antibody inhibits imatinib-resistant gastrointestinal stromal tumor growth.
abstract: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract and arises from the interstitial cells of Cajal. It is characterized by expression of the receptor tyrosine kinase CD117 (KIT). In 70-80% of GIST cases, oncogenic mutations in KIT are present, leading to constitutive activation of the receptor, which drives the proliferation of these tumors. Treatment of GIST with imatinib, a small-molecule tyrosine kinase inhibitor, inhibits KIT-mediated signaling and initially results in disease control in 70-85% of patients with KIT-positive GIST. However, the vast majority of patients eventually develop resistance to imatinib treatment, leading to disease progression and posing a significant challenge in the clinical management of these tumors. Here, we show that an anti-KIT monoclonal antibody (mAb), SR1, is able to slow the growth of three human GIST cell lines in vitro. Importantly, these reductions in cell growth were equivalent between imatinib-resistant and imatinib-sensitive GIST cell lines. Treatment of GIST cell lines with SR1 reduces cell-surface KIT expression, suggesting that mAb-induced KIT down-regulation may be a mechanism by which SR1 inhibits GIST growth. Furthermore, we also show that SR1 treatment enhances phagocytosis of GIST cells by macrophages, indicating that treatment with SR1 may enhance immune cell-mediated tumor clearance. Finally, using two xenotransplantation models of imatinib-sensitive and imatinib-resistant GIST, we demonstrate that SR1 is able to strongly inhibit tumor growth in vivo. These results suggest that treatment with mAbs targeting KIT may represent an alternative, or complementary, approach for treating GIST.
authors: Department of Pathology, Stanford University Medical Center, Stanford, CA 94305, USA.
authors: Badreddin
authors: B
authors: Edris
authors: Stephen B
authors: SB
authors: Willingham
authors: Kipp
authors: K
authors: Weiskopf
authors: Anne K
authors: AK
authors: Volkmer
authors: Jens-Peter
authors: JP
authors: Volkmer
authors: Thomas
authors: T
authors: Mühlenberg
authors: Kelli D
authors: KD
authors: Montgomery
authors: Humberto
authors: H
authors: Contreras-Trujillo
authors: Agnieszka
authors: A
authors: Czechowicz
authors: Jonathan A
authors: JA
authors: Fletcher
authors: Robert B
authors: RB
authors: West
authors: Irving L
authors: IL
authors: Weissman
authors: Matt
authors: M
authors: van de Rijn
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D000068877:Imatinib Mesylate; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010587:Phagocytosis / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit
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