Tyrosine phosphoproteomics of patient-derived xenografts reveals ephrin type-b receptor 4 tyrosine kinase as a therapeutic target in pancreatic cancer

Renuse Santosh, Vijay S. Madamsetty, Dong Gi Mun, Anil K. Madugundu, Smrita Singh, Savita Udainiya, Kiran K. Mangalaparthi, Min Sik Kim, Ren Liu, S. Ram Kumar, Valery Krasnoperov, Mark Truty, Rondell P. Graham, Parkash S. Gill, Debabrata Mukhopadhyay, Akhilesh Pandey

Research output: Contribution to journalArticlepeer-review

Abstract

Pancreatic ductal adenocarcinoma is a recalcitrant tumor with minimal response to conventional chemotherapeutic approaches. Oncogenic signaling by activated tyrosine kinases has been implicated in cancers resulting in activation of diverse effector signaling pathways. Thus, the discovery of aberrantly activated tyrosine kinases is of great interest in developing novel therapeutic strategies in the treatment and management of pancreatic cancer. Patient-derived tumor xenografts (PDXs) in mice serve as potentially valuable preclinical models as they maintain the histological and molecular heterogeneity of the original human tumor. Here, we employed high-resolution mass spectrometry combined with immunoaffinity purification using anti-phosphotyrosine antibodies to profile tyrosine phosphoproteome across 13 pancreatic ductal adenocarcinoma PDX models. This analysis resulted in the identification of 1199 tyrosine-phosphorylated sites mapping to 704 proteins. The mass spectrometric analysis revealed widespread and heterogeneous activation of both receptor and non-receptor tyrosine kinases. Preclinical studies confirmed ephrin type-B receptor 4 (EphB4) as a potential therapeutic target based on the efficacy of human serum albumin-conjugated soluble EphB4 in mice bearing orthotopic xenografts. Immunohistochemistry-based validation using tissue microarrays from 346 patients with PDAC showed significant expression of EphB4 in >70% of patients. In summary, we present a comprehensive landscape of tyrosine phosphoproteome with EphB4 as a promising therapeutic target in pancreatic ductal adenocarcinoma.

Original languageEnglish (US)
Article number3404
JournalCancers
Volume13
Issue number14
DOIs
StatePublished - Jul 2 2021

Keywords

  • EphB4
  • Personalized medicine
  • Receptor tyrosine kinase
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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