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Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies
Alison M Kurimchak1, Vikas Kumar1, Carlos Herrera-Montávez1
1Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Abstract:
Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States, with limited effective targeted therapies. Endometrial tumors exhibit frequent alterations in protein kinases, yet only a small fraction of the kinome has been therapeutically explored. To identify kinase therapeutic avenues for EC, we profiled the kinome of endometrial tumors and normal endometrial tissues using Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). Our proteomics analysis identified a network of kinases overexpressed in tumors, including Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1). Immunohistochemical (IHC) analysis of endometrial tumors confirmed MIB-MS findings and showed SRPK1 protein levels were highly expressed in endometrioid and uterine serous cancer (USC) histological subtypes. Moreover, querying large-scale genomics studies of EC tumors revealed high expression of SRPK1 correlated with poor survival. Loss-of-function studies targeting SRPK1 in an established USC cell line demonstrated SRPK1 was integral for RNA splicing, as well as cell cycle progression and survival under nutrient deficient conditions. Profiling of USC cells identified a compensatory response to SRPK1 inhibition that involved EGFR and the up-regulation of IGF1R and downstream AKT signaling. Co-targeting SRPK1 and EGFR or IGF1R synergistically enhanced growth inhibition in serous and endometrioid cell lines, representing a promising combination therapy for EC.
Insights
Targeting Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1) shows promise for endometrial cancer. Combination therapies targeting SRPK1 with EGFR or IGF1R enhance growth inhibition in cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Endometrial carcinoma (EC) is a common gynecologic malignancy with limited targeted therapies.
- Protein kinase alterations are frequent in EC, but the therapeutic potential of most kinases remains unexplored.
Purpose of the Study:
- To identify novel kinase targets for EC therapy.
- To investigate the role of Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1) in EC progression and survival.
Main Methods:
- Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS) to profile the kinome of endometrial tumors and normal tissues.
- Immunohistochemistry (IHC) to validate SRPK1 expression.
- Loss-of-function studies in EC cell lines.
- Genomic data analysis to correlate SRPK1 expression with survival.
Main Results:
- MIB-MS identified a network of overexpressed kinases in EC, including SRPK1.
- High SRPK1 protein levels were observed in endometrioid and uterine serous cancer (USC) subtypes and correlated with poor survival.
- SRPK1 is crucial for RNA splicing, cell cycle progression, and survival under nutrient deficiency in USC cells.
- Inhibition of SRPK1 led to compensatory activation of EGFR, IGF1R, and AKT signaling.
Conclusions:
- SRPK1 is a potential therapeutic target for endometrial carcinoma.
- Co-targeting SRPK1 with EGFR or IGF1R demonstrates synergistic anti-cancer effects in EC cell lines.
- Combination therapy targeting SRPK1 and EGFR or IGF1R represents a promising strategy for EC treatment.
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