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Expression of imatinib mesylate-targeted kinases in endometrial carcinoma
Brian M Slomovitz1, Russell R Broaddus, Rosemarie Schmandt
1Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Purpose:
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.
Experimental Design:
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.
Insights
This study found that Abl and PDGFR are highly expressed in most endometrial cancers. These findings suggest imatinib mesylate could be a potential treatment for endometrial carcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Imatinib mesylate targets tyrosine kinases like Abl, c-Kit, and PDGFR.
- It is an effective treatment for chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST).
- Endometrial cancer is characterized by specific genetic mutations, prompting investigation into targeted therapies.
Purpose of the Study:
- To assess the expression of Abl, c-Kit, and PDGFR in primary and recurrent endometrial carcinoma.
- To determine the potential of imatinib mesylate as a treatment for endometrial cancer.
Main Methods:
- Immunohistochemical analysis was performed on 63 endometrial carcinoma samples (EEC and UPSC, primary and recurrent).
- Antibodies for Abl, PDGFR, c-Kit, and their phosphorylated forms were used for staining.
- Expression levels were correlated with tumor type, grade, and recurrence.
Main Results:
- Abl and PDGFR were highly expressed in both primary and recurrent EEC and UPSC.
- c-Kit expression was minimal in primary tumors but present in some recurrent tumors.
- Phosphorylated Abl and PDGFR were also widely detected in tumor samples.
- Lower grade EEC tumors showed significantly higher PDGFR expression.
Conclusions:
- The high prevalence of Abl and PDGFR expression in endometrial carcinomas supports their potential as therapeutic targets.
- Preclinical data indicate that imatinib mesylate may offer a viable treatment option for patients with endometrial cancer.
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