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Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 As Candidate Therapeutic Target
Mol Cell Proteomics. 2020 Dec;19(12) :2068-2089
PMID: 32994315    PMCID: PMC7710141    URL: https://www.ncbi.nlm.nih.gov/pubmed/32994315
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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 upregulation 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.
Notes
1535-9484 Kurimchak, Alison M Kumar, Vikas Orcid: 0000-0001-7513-6832 Herrera-Montávez, Carlos Johnson, Katherine J Srivastava, Nishi Devarajan, Karthik Peri, Suraj Cai, Kathy Qi Mantia-Smaldone, Gina M Duncan, James S Orcid: 0000-0002-1276-2745 Journal Article United States Mol Cell Proteomics. 2020 Sep 29:mcp.RA120.002012. doi: 10.1074/mcp.RA120.002012.