Overexpression of the KIT/SCF in uveal melanoma does not translate into clinical efficacy of imatinib mesylate.
OBJECTIVE
Recently, gene amplification and overexpression of KIT as well as activating mutations in the KIT gene have been described to occur in certain subsets of melanoma. These findings suggest KIT as a potential target for therapy with imatinib mesylate in these melanomas. To date, data on the KIT status in uveal melanoma (UM) is limited.


METHODS
We analyzed the expression of the KIT protein (CD117, c-kit) and its ligand, stem cell factor (SCF), in primary and metastatic UM.


RESULTS
By immunohistochemistry, SCF-positive tumor cells (>90%) were detectable in 43% of primary UM and in 58% of UM metastases. Strong expression of KIT (>90%) in tumor cells was present in 55% of primary UM and in 76% of UM metastases. This overexpression of both KIT and SCF suggests the clinical application of imatinib mesylate in metastatic UM. This notion was tested in a clinical study using Simon's two-stage design. Patients received imatinib (600 mg p.o. daily) until progress or unacceptable toxicities. The trial did not enter stage II as no objective response was observed in the first group. This observation prompted further molecular analysis, which revealed no mutations in the genomic sequence of KIT in exons 11, 13, 17, and 18. Moreover, the mitogen-activated protein kinase pathway was not activated in any of the tumors as measured by ERK phosphorylation.


CONCLUSIONS
These results show the lack of clinical effectiveness of imatinib in UM, which was originally anticipated based on the high levels of KIT and SCF expression.
Hofmann
Uta B
UB
Department of Dermatology, Julius Maximilians University, Würzburg, Germany.
Kauczok-Vetter
Claudia S
CS
Houben
Roland
R
Becker
Jürgen C
JC
D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D008875:Middle Aged; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use*; D019089:Stem Cell Factor / Q000378:metabolism; D015854:Up-Regulation; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit