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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
07:42

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Published on: September 19, 2018

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Understand the acquired resistance of RTK inhibitors by computational receptor tyrosine kinases network

Yuanxin Tian1, Yunci Ma2, Shaoyu Wu1

  • 1Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, People's Republic of China.

Computational Biology and Chemistry
|August 13, 2018
PubMed

Insights

Drug resistance to Receptor Tyrosine Kinase (RTK) inhibitors is a major challenge. Our network analysis reveals RTKs as key controllers, with Rap1, Ras, and PI3K/Akt pathways contributing to resistance via crosstalk.

Area of Science:

  • Oncology
  • Systems Biology
  • Pharmacology

Background:

  • Receptor Tyrosine Kinase (RTK) inhibitors are vital anti-cancer therapeutics.
  • Acquired drug resistance remains a significant clinical challenge, limiting treatment efficacy.

Purpose of the Study:

  • To investigate the protein-protein interaction network of RTKs to understand mechanisms of drug resistance.
  • To identify key signaling pathways involved in resistance to RTK inhibitors.

Main Methods:

  • Construction and analysis of a protein-protein interaction network involving 1334 proteins and 2623 interactions from 52 RTKs.
  • KEGG pathway analysis to identify relevant signaling cascades.

Main Results:

  • RTK proteins were identified as central controllers within the protein-protein interaction network.
  • Interactions within a shortest path of 2 from RTKs were frequently associated with drug resistance.
  • The Rap1 signaling pathway, alongside the known Ras and PI3K/Akt pathways, was implicated in RTK inhibitor resistance.

Conclusions:

  • RTK-centric network analysis provides a global view of drug resistance mechanisms.
  • Pathway crosstalk, including Rap1, Ras, and PI3K/Akt, contributes to acquired resistance.
  • Findings suggest potential combination strategies targeting multiple pathways for enhanced RTK inhibitor efficacy.
Keywords:
Network analysisProtein-protein interactionResistanceTyrosine kinase inhibitors

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