Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 as Candidate Therapeutic Target

Alison M. Kurimchak, Vikas Kumar, Carlos Herrera-Montávez, Katherine J. Johnson, Nishi Srivastava, Karthik Devarajan, Suraj Peri, Kathy Cai, Gina M. Mantia-Smaldone, James S. Duncan

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish
Pages (from-to)2068-2090
Number of pages22
JournalMolecular and Cellular Proteomics
Volume19
Issue number12
DOIs
StatePublished - Dec 1 2020

Keywords

  • Apoptosis/drug effects
  • Cell Cycle/genetics
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Cell Survival/genetics
  • Endometrial Neoplasms/enzymology
  • ErbB Receptors/antagonists & inhibitors
  • Female
  • Humans
  • Mass Spectrometry
  • Molecular Targeted Therapy
  • Neoplasms, Cystic, Mucinous, and Serous/pathology
  • Prognosis
  • Protein Kinase Inhibitors/pharmacology
  • Protein Kinases/metabolism
  • Protein Serine-Threonine Kinases/antagonists & inhibitors
  • Proteogenomics
  • Proteomics
  • RNA Splicing/genetics
  • Receptor, IGF Type 1/antagonists & inhibitors
  • Survival Analysis
  • Uterine Neoplasms/pathology

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