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Inhibition of Autophagy Reveals ATR Protein Kinase as a Key Mediator of Cisplatin Sensitivity in Osteosarcoma

Janice S Pereira1, Gabriel Rosa1, Aine Pears1

  • 1Department of Natural Sciences, Faculty of Science & Technology, Middlesex University, London, UK.

Cancer Medicine
|March 6, 2026
PubMed
Abstract

Insights

Autophagy enhances chemoresistance in osteosarcoma (OS). Inhibiting ATR (Ataxia Telangiectasia and Rad3-related protein) blocks DNA damage signaling and autophagy, improving cisplatin sensitivity in OS cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Osteosarcoma (OS) is the most common primary bone cancer.
  • Chemotherapy resistance in OS leads to poor patient outcomes.
  • The role of autophagy in OS chemoresistance requires further investigation.

Purpose of the Study:

  • To investigate the role of autophagy in osteosarcoma chemoresistance.
  • To identify upstream regulators linking DNA damage signaling, autophagy, and chemoresistance.
  • To evaluate ATR as a potential therapeutic target for enhancing chemotherapy sensitivity in OS.

Main Methods:

  • Analysis of autophagy levels in OS tumors of varying grades and stages.
  • Assessment of cisplatin (CIS) sensitivity in HOS-143B cells with and without autophagy inhibition (ATG7 knockout).
  • Kinase screening to identify signaling pathways affected by autophagy inhibition.
  • Investigation of ATR's role in p53 phosphorylation, DNA Damage Response (DDR), and autophagy.

Main Results:

  • Elevated autophagy levels correlate with advanced OS and poorer outcomes.
  • Autophagy inhibition via ATG7 knockout significantly enhances CIS sensitivity in OS cells.
  • ATR inhibition increases CIS sensitivity by promoting apoptosis, reducing p53 phosphorylation, and blocking autophagy in CIS-treated OS cells.

Conclusions:

  • ATR inhibition represents a novel therapeutic strategy for osteosarcoma.
  • Targeting ATR simultaneously disrupts DNA damage signaling and autophagy, enhancing CIS sensitivity.
  • ATR inhibition may reduce chemotherapy dosage, limit toxicity, and improve survival for OS patients.
Keywords:
ATG7ATRautophagychemoresistanceosteosarcoma

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