2. Academic Validation
  3. ATM functions as a rheostat of metabolic stress in small-cell lung cancer

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

  • bioRxiv. 2026 Mar 17:2026.03.13.711672. doi: 10.64898/2026.03.13.711672.
Debdatta Halder 1,  Utsav Sen 1,  Vrinda Jethalia 1 2 3,  Subhamoy Chakraborty 4,  Andrew Elliott 5,  Kedwin Ventura 1,  Ari Vanderwalde 5,  Balazs Halmos 6,  Hossein Borghaei 7,  Tin Htwe Thin 8,  Alan Soto 8,  Mirela Berisa 9,  Rachel Brody 8,  Deniz Demircioglu 1 2 3,  Dan Hasson 1 2 3,  Triparna Sen 4
Affiliations

Affiliations

  • 1 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 2 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3 Bioinformatics for Next Generation Sequencing (BiNGS) Core, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4 Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
  • 5 Caris Life Sciences, Phoenix, AZ, USA.
  • 6 Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY, USA.
  • 7 Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
  • 8 Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 9 Metabolomics Core, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
PMID: 41890037 DOI: 10.64898/2026.03.13.711672
Abstract

ATM is best known as a guardian of genomic stability, yet its contributions to oncogenic signaling in aggressive malignancies like small-cell lung Cancer (SCLC) remain poorly understood. Despite ATM being an established clinical vulnerability in SCLC, its influence on dysregulated tumorigenic circuits remains unclear. We demonstrate that inhibition of ATM disrupts the AKT-mTORC1-4EBP1 signaling axis, leading to attenuation of the master regulator of stress, ATF4. ATF4 and MYC appear to co-regulate one another in a feedback loop critical for redox homeostasis. ATM inhibition perturbs both the expression and function of MYC and ATF4, leading to increased intracellular Reactive Oxygen Species, impaired glutathione recycling, and ferroptotic cell death, thereby exposing a crucial dependency of SCLC on stress-adaptive signaling. We uncover previously unrecognized metabolic vulnerability in SCLC, nominating ATM as a regulator of adaptive stress, expanding its role beyond canonical DNA damage repair (DDR) and highlighting therapeutically exploitable opportunities in aggressive tumors.

Keywords

ATF4; ATM; Ferroptosis; GSH; ISR; MYC; ROS; metabolic rewiring; oncogenic signaling; small-cell lung cancer.

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