Expression of imatinib mesylate-targeted kinases in endometrial carcinoma.
OBJECTIVE
Imatinib mesylate is a tyrosine kinase inhibitor that specifically targets c-Kit, Abl, and platelet-derived growth factor receptor (PDGFR). It has been shown to be an effective treatment for patients with chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). These cancers are characterized by activating mutations of the Abl and c-Kit tyrosine kinases, respectively. To determine whether imatinib mesylate could be a potentially useful agent in the treatment of endometrial cancer, we assessed the expressions of Abl, c-Kit, and PDGFR in both primary and recurrent endometrial carcinoma.


METHODS
We performed immunohistochemical analysis on formalin-fixed, paraffin-embedded sections from 63 patients: 33 with endometrioid endometrial carcinoma (EEC), 11 with uterine papillary serous carcinoma (UPSC), 12 with recurrent EEC, and seven with recurrent UPSC. The sections were stained with commercially available antibodies for Abl, PDGFR, and c-Kit. The sections were also stained for phosphorylated Abl and phosphorylated PDGFR.


RESULTS
Among the primary EEC, 28/33 (85%) stained positively for Abl and 30/33 (91%) were positive for PDGFR. Of the primary UPSC, 8/11 (73%) were positive for Abl. In addition, 8/11 (73%) of the primary UPSC tumors were positive for PDGFR. Neither the primary EEC (0/33) nor the primary UPSC (0/11) expressed c-Kit. Of the recurrent EEC tumors, 11/12 (92%) were positive for Abl expression, 12/12 (100%) were positive for PDGFR, and 2/8 (25%) were positive for c-Kit. Of the recurrent UPSC, 6/7 (86%) were positive for Abl, 7/7 (100%) were positive for PDGFR, and 2/4 (50%) for c-Kit. In addition, the majority of primary and recurrent tumors were positive for phosphorylated Abl (primary EEC, 91%; primary UPSC, 64%; recurrent EEC, 83%; recurrent UPSC, 86%), and phosphorylated PDGFR (primary EEC, 46%; primary UPSC, 40%; recurrent EEC, 58%; recurrent UPSC, 100%). Within the EEC primary tumors, the differences in kinase expression by grade of tumor were not significant except for PDGFR kinase; the lower grade tumors (1 and 2) had more PDGFR expression than the grade 3 tumors (P < 0.05).


CONCLUSIONS
The majority of primary and recurrent EEC, as well as primary and recurrent UPSC express Abl and PDGFR. This preclinical data suggest that imatinib mesylate may be useful in the treatment of patients with endometrial carcinoma.
Slomovitz
Brian M
BM
Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Broaddus
Russell R
RR
Schmandt
Rosemarie
R
Wu
Weiguo
W
Oh
Jonathan C
JC
Ramondetta
Lois M
LM
Burke
Thomas W
TW
Gershenson
David M
DM
Lu
Karen H
KH
D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D016612:Paraffin Embedding; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor; D016315:Proto-Oncogene Proteins c-abl