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1.
J Clin Invest ; 127(6): 2310-2325, 2017 Jun 01.
Article in English | MEDLINE | ID: mdl-28463229

ABSTRACT

Identification and functional validation of oncogenic drivers are essential steps toward advancing cancer precision medicine. Here, we have presented a comprehensive analysis of the somatic genomic landscape of the widely used BRAFV600E- and NRASQ61K-driven mouse models of melanoma. By integrating the data with publically available genomic, epigenomic, and transcriptomic information from human clinical samples, we confirmed the importance of several genes and pathways previously implicated in human melanoma, including the tumor-suppressor genes phosphatase and tensin homolog (PTEN), cyclin dependent kinase inhibitor 2A (CDKN2A), LKB1, and others. Importantly, this approach also identified additional putative melanoma drivers with prognostic and therapeutic relevance. Surprisingly, one of these genes encodes the tyrosine kinase FES. Whereas FES is highly expressed in normal human melanocytes, FES expression is strongly decreased in over 30% of human melanomas. This downregulation correlates with poor overall survival. Correspondingly, engineered deletion of Fes accelerated tumor progression in a BRAFV600E-driven mouse model of melanoma. Together, these data implicate FES as a driver of melanoma progression and demonstrate the potential of cross-species oncogenomic approaches combined with mouse modeling to uncover impactful mutations and oncogenic driver alleles with clinical importance in the treatment of human cancer.


Subject(s)
Melanoma/genetics , Proto-Oncogene Proteins c-fes/genetics , Skin Neoplasms/genetics , Animals , Cell Line, Tumor , Cell Proliferation , DNA Copy Number Variations , Genes, Tumor Suppressor , Genomics , Humans , Melanoma/metabolism , Mice, Inbred C57BL , Mice, Nude , Mice, Transgenic , Neoplasm Transplantation , Oncogenes , Proto-Oncogene Proteins c-fes/metabolism , Skin Neoplasms/metabolism , Wnt Signaling Pathway
2.
Oncotarget ; 7(32): 51163-51173, 2016 Aug 09.
Article in English | MEDLINE | ID: mdl-27323399

ABSTRACT

CDK4/CDK6 and RB proteins drive the progression through the G1 phase of the cell cycle. In acute myeloid leukemia (AML), the activity of the CDK/Cyclin D complex is increased. The mechanism involved is unknown, as are the respective roles played by CDK4 or CDK6 in this process. Here, we report that AML cells carrying FLT3-ITD mutations are dependent on CDK6 for cell proliferation while CDK4 is not essential. We showed that FLT3-ITD signaling is responsible for CDK6 overexpression, through a pathway involving the SRC-family kinase HCK. Accordingly, FLT3-ITD failed to transform primary hematopoietic progenitor cells from Cdk6-/- mice. Our results demonstrate that CDK6 is the primary target of CDK4/CDK6 inhibitors in FLT3-ITD positive AML. Furthermore, we delineate an essential protein kinase pathway -FLT3/HCK/CDK6- in the context of AML with FLT3-ITD mutations.


Subject(s)
Cyclin-Dependent Kinase 6/genetics , Leukemia, Myeloid, Acute/genetics , Proto-Oncogene Proteins c-hck/genetics , fms-Like Tyrosine Kinase 3/genetics , Animals , Cell Line, Tumor , Cyclin-Dependent Kinase 6/metabolism , Gene Expression Regulation, Leukemic , Humans , Leukemia, Myeloid, Acute/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutation , Proto-Oncogene Proteins c-hck/metabolism , Signal Transduction/genetics , Tandem Repeat Sequences , fms-Like Tyrosine Kinase 3/metabolism
3.
JAMA Dermatol ; 150(12): 1345-9, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25317746

ABSTRACT

IMPORTANCE The KIT receptor is mutated in approximately 15%of acral, mucosal, and chronic, sun-damaged melanomas. The status of KIT mutations is of interest because they usually are mutually exclusive with N-RAS and B-RAF mutations and because of the availability of KIT kinase inhibitors in the clinic. Some recurrent KIT mutations are well characterized; others are poorly described.OBSERVATIONS We describe a novel KIT mutation in a patient with metastatic melanoma. The mutation, located in exon 13, resulted in S628N substitution in the KIT receptor. Using all-atom molecular dynamics simulations, biochemical assays, and cell-based assays, we showed that the mutation is a bona fide gain-of-function oncogenic mutation. Furthermore,we evaluated the sensitivity of the mutant to imatinib and dasatinib.CONCLUSIONS AND RELEVANCE We report a novel KIT gain-of-function mutation with S628N substitution (exon 13) and show that it is sensitive to imatinib in vitro. Therefore, patients with this mutation may be eligible for KIT kinase inhibitor­based therapy. Further studies are needed to evaluate the clinical benefit of such therapy.


Subject(s)
Cell Transformation, Neoplastic/genetics , Lung Neoplasms/genetics , Melanoma/genetics , Proto-Oncogene Proteins c-kit/genetics , Skin Neoplasms/genetics , Spinal Neoplasms/genetics , Aged, 80 and over , Animals , Benzamides/pharmacology , Cells, Cultured , Colony-Forming Units Assay , Dasatinib , Fatal Outcome , Female , Fibroblasts/cytology , Humans , Imatinib Mesylate , Lung Neoplasms/secondary , Melanoma/secondary , Mutation, Missense , Phosphorylation/drug effects , Piperazines/pharmacology , Point Mutation , Proto-Oncogene Proteins c-kit/metabolism , Pyrimidines/pharmacology , Rats , Skin Neoplasms/pathology , Spinal Neoplasms/secondary , Thiazoles/pharmacology
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