IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma.
OBJECTIVE
IL2 inducible T-cell kinase (ITK) promoter CpG sites are hypomethylated in melanomas compared with nevi. The expression of ITK in melanomas, however, has not been established and requires elucidation.


METHODS
An ITK-specific monoclonal antibody was used to probe sections from deidentified, formalin-fixed paraffin-embedded tumor blocks or cell line arrays and ITK was visualized by IHC. Levels of ITK protein differed among melanoma cell lines and representative lines were transduced with four different lentiviral constructs that each contained an shRNA designed to knockdown ITK mRNA levels. The effects of the selective ITK inhibitor BI 10N on cell lines and mouse models were also determined.


RESULTS
ITK protein expression increased with nevus to metastatic melanoma progression. In melanoma cell lines, genetic or pharmacologic inhibition of ITK decreased proliferation and migration and increased the percentage of cells in the G0-G1 phase. Treatment of melanoma-bearing mice with BI 10N reduced growth of ITK-expressing xenografts or established autochthonous (Tyr-Cre/Pten(null)/Braf(V600E)) melanomas.


CONCLUSIONS
We conclude that ITK, formerly considered an immune cell-specific protein, is aberrantly expressed in melanoma and promotes tumor development and progression. Our finding that ITK is aberrantly expressed in most metastatic melanomas suggests that inhibitors of ITK may be efficacious for melanoma treatment. The efficacy of a small-molecule ITK inhibitor in the Tyr-Cre/Pten(null)/Braf(V600E) mouse melanoma model supports this possibility.
Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina.
Craig C
CC
Carson
Department of Medicine, The University of North Carolina, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina.
Stergios J
SJ
Moschos
Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina.
Sharon N
SN
Edmiston
Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina.
David B
DB
Darr
Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina.
Nana
N
Nikolaishvili-Feinberg
Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, North Carolina.
Pamela A
PA
Groben
Department of Biostatistics, The University of North Carolina, Chapel Hill, North Carolina.
Xin
X
Zhou
Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Biostatistics, The University of North Carolina, Chapel Hill, North Carolina.
Pei Fen
PF
Kuan
Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina.
Shaily
S
Pandey
Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina.
Keefe T
KT
Chan
Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina.
Jamie L
JL
Jordan
Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina.
Honglin
H
Hao
Department of Surgery, The University of North Carolina, Chapel Hill, North Carolina.
Jill S
JS
Frank
Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina.
Dennis A
DA
Hopkinson
Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina.
David C
DC
Gibbs
Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina.
Virginia D
VD
Alldredge
Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina.
Eloise
E
Parrish
Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina.
Sara C
SC
Hanna
Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina.
Paula
P
Berkowitz
Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina.
David S
DS
Rubenstein
Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Pathology and Laboratory Medicine, The University of North Carolina, Chapel Hill, North Carolina. Department of Neurology, The University of North Carolina, Chapel Hill, North Carolina. Neuroscience Center, The University of North Carolina, Chapel Hill, North Carolina.
C Ryan
CR
Miller
Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Cell Biology and Physiology, The University of North Carolina, Chapel Hill, North Carolina.
James E
JE
Bear
Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Surgery, The University of North Carolina, Chapel Hill, North Carolina.
David W
DW
Ollila
Department of Medicine, The University of North Carolina, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina.
Norman E
NE
Sharpless
Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. Department of Epidemiology, The University of North Carolina, Chapel Hill, North Carolina.
Kathleen
K
Conway
Department of Dermatology, The University of North Carolina, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina. nthomas@med.unc.edu.
Nancy E
NE
Thomas
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D055785:Gene Knockdown Techniques; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase