2. Academic Validation
  3. Cabozantinib Sensitizes NSCLC Cells to Radiation by Inducing Ferroptosis via STAT3/MCL1/BECN1/SLC7A11 Axis Suppression

Cabozantinib Sensitizes NSCLC Cells to Radiation by Inducing Ferroptosis via STAT3/MCL1/BECN1/SLC7A11 Axis Suppression

  • Cancers (Basel). 2025 Sep 9;17(18):2950. doi: 10.3390/cancers17182950.
Cheng-Yi Wang 1,  Chao-Yuan Huang 2,  Li-Ju Chen 2,  Grace Chen 3,  Shiao-Ya Hong 4
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 231009, Taiwan.
  • 2 Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100229, Taiwan.
  • 3 School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan.
  • 4 Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
PMID: 41008795 DOI: 10.3390/cancers17182950
Abstract

Background/objectives: Intrinsic radioresistance in non-small-cell lung Cancer (NSCLC) is partially driven by adaptive redox mechanisms that prevent oxidative cell death. Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a potential therapeutic vulnerability in tumors with elevated antioxidant capacity. However, its mechanistic integration with radiotherapy remains incompletely understood.

Methods: We compared the effects of three clinically approved VEGFR-targeting tyrosine kinase inhibitors (TKIs), cabozantinib, lenvatinib, and ripretinib, on NSCLC cell viability with and without radiation. Subsequent mechanistic studies focused on cabozantinib and included Ferroptosis rescue assays (ferrostatin-1, deferoxamine), lipid ROS quantification, glutathione assays, clonogenic survival, co-immunoprecipitation of BECN1-SLC7A11 complexes, and BECN1 knockdown by siRNA and shRNA.

Results: All three TKIs were evaluated for cytotoxicity, but only cabozantinib significantly reduced NSCLC cell viability in combination with radiation in a ferroptosis-dependent manner. Cabozantinib inhibited STAT3 phosphorylation and downregulated MCL1, resulting in the release of BECN1. This allowed BECN1 to bind and suppress SLC7A11, disrupting system Xc- function, depleting glutathione, and promoting lipid ROS accumulation. Genetic silencing of BECN1 reversed these effects and restored redox balance and clonogenic capacity. Lenvatinib and ripretinib failed to elicit similar responses, indicating that the inhibition of non-VEGFR targets (e.g., MET, Axl) may be essential for Ferroptosis induction by cabozantinib.

Conclusions: Cabozantinib enhances the radiosensitization of NSCLC cells through Ferroptosis induction mediated by the suppression of the STAT3/MCL1/BECN1/SLC7A11 axis. These findings uncover a novel mechanism linking kinase inhibition to redox imbalance and suggest that the pharmacologic modulation of Ferroptosis using multi-target TKIs may represent a rational approach to overcome radioresistance in NSCLC.

Keywords

BECN1; MCL1; NSCLC; SLC7A11; STAT3; cabozantinib; ferroptosis; radiotherapy.

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