Pharmacological inhibitors of c-KIT block mutant c-KIT mediated migration of melanocytes and melanoma cells in vitro and in vivo.
Mutations in the receptor tyrosine kinase c-KIT (KIT) are frequent oncogenic alterations in melanoma and are predominantly detected in tumors of acral, mucosal, and chronically sun-damaged skin. Research indicates that melanocytes with aberrant KIT signaling can be found in the distant periphery of the primary tumor; However, it is hitherto unknown whether KIT might confer a migratory advantage, thereby enabling genetically abnormal cells to populate a distal area. In this study, we investigated the role of mutant KIT in melanocyte- and melanoma cell migration using KIT mutant lines as well as genetically manipulated murine and primary human melanocytes. Our results revealed that melanocytes, stably transduced with mutant KIT closed a gap inflicted on cell monolayers faster than wild-type controls. Similarly, KIT mutant human melanoma lines were able to populate a larger area in a 3D in vitro skin model compared to KIT wild type and BRAF mutant lines. Genomic profiling revealed that genes associated with increased cell-dispersal of KIT mutant variants were linked to a statistically significant up-regulation of 60 migratory genes (z-score 1.334; p=0.0001). In addition, in vivo experiments harnessing a mouse xenograft model of early melanoma development demonstrated rapid lateral migration of KIT mutant cells compared to respective controls. The specific kinase inhibitors imatinib and nilotinib, could abrogate this migratory advantage in vitro and in vivo. Our work suggests that KIT inhibition might help to target migratory active, KIT mutant melanoma cells, thus representing a potential strategy to reduce spread and local recurrence.
Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.|Department of Dermatology, The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria.|School of Medicine, Sigmund Freud University, Vienna, Austria.|Children's Cancer Research Institute, St. Anna Kinderspital, Vienna, Austria.
Christian
C
Posch
Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.
Homayoun
H
Moslehi
Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.|Department of Medical Sciences, Section of Dermatology, University of Turin, Turin, Italy.
Martina
M
Sanlorenzo
Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.
Gary
G
Green
Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.|Department of Dermatology, The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria.|School of Medicine, Sigmund Freud University, Vienna, Austria.
Igor
I
Vujic
Children's Cancer Research Institute, St. Anna Kinderspital, Vienna, Austria.
Renate
R
Panzer-Grümayer
Department of Dermatology, The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria.|School of Medicine, Sigmund Freud University, Vienna, Austria.
Klemens
K
Rappersberger
Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA.
Susana
S
Ortiz-Urda
D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; C498826:nilotinib
kinase; kinome; melanoma; migration; targeted therapy