Pharmacological inhibitors of c-KIT block mutant c-KIT mediated migration of melanocytes and melanoma cells in vitro and in vivo
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Christian Posch1,2,3,4, Homayoun Moslehi1, Martina Sanlorenzo1,5, Gary Green1, Igor Vujic1,2,3, Renate Panzer-Grümayer4, Klemens Rappersberger2,3, Susana Ortiz-Urda1
1Department of Dermatology, Mt. Zion Cancer Research Center, University of California San Francisco, San Francisco, CA, USA
2Department of Dermatology, The Rudolfstiftung Hospital, Academic Teaching Hospital, Medical University Vienna, Vienna, Austria
3School of Medicine, Sigmund Freud University, Vienna, Austria
4Children’s Cancer Research Institute, St. Anna Kinderspital, Vienna, Austria
5Department of Medical Sciences, Section of Dermatology, University of Turin, Turin, Italy
Susana Ortiz-Urda, email: [email protected]
Keywords: targeted therapy, kinase, kinome, melanoma, migration
Received: October 24, 2015 Accepted: June 01, 2016 Published: June 14, 2016
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.
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