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Updated: Mar 28, 2026

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ATM functions as a rheostat of metabolic stress in small-cell lung cancer

Debdatta Halder1, Utsav Sen1, Vrinda Jethalia1,2,3

  • 1Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Biorxiv : the Preprint Server for Biology
|March 27, 2026
PubMed

Insights

ATM inhibition disrupts stress-adaptive signaling in small-cell lung cancer (SCLC), leading to ferroptosis. This reveals a new metabolic vulnerability and therapeutic target beyond DNA damage repair in aggressive tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • ATM is crucial for genomic stability but its role in SCLC oncogenic signaling is unclear.
  • SCLC's metabolic landscape and interaction with signaling networks are poorly understood, hindering treatment strategies.

Purpose of the Study:

  • To investigate ATM's role in SCLC oncogenic signaling and metabolic adaptation.
  • To identify novel therapeutic vulnerabilities in SCLC by understanding ATM's function beyond DNA damage repair.

Main Methods:

  • Inhibition of ATM in SCLC models.
  • Analysis of AKT-mTORC1-4EBP1 signaling axis and ATF4/MYC feedback loop.
  • Assessment of reactive oxygen species, glutathione recycling, and ferroptosis.

Main Results:

  • ATM inhibition disrupts the AKT-mTORC1-4EBP1 axis and attenuates ATF4.
  • ATM inhibition perturbs ATF4 and MYC co-regulation, impacting redox homeostasis.
  • ATM inhibition increases ROS, impairs glutathione recycling, and induces ferroptosis in SCLC cells.

Conclusions:

  • ATM regulates adaptive stress responses and metabolic rewiring in SCLC, expanding its known functions.
  • ATM inhibition exposes a critical dependency of SCLC on stress-adaptive signaling, offering therapeutic opportunities.
  • Targeting ATM presents a novel strategy for aggressive SCLC by exploiting its metabolic vulnerabilities.
Keywords:
ATF4ATMFerroptosisGSHISRMYCROSmetabolic rewiringoncogenic signalingsmall-cell lung cancer

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