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S6K1 Modulates STAT3 Activation to Promote Resistance to Radiotherapy in Lung Cancer.

Ali Calderon-Aparicio1, Noelle Francois1, Tyler Grenda2

  • 1Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

International Journal of Molecular Sciences
|February 27, 2026
PubMed
Summary

Targeting S6K1 (a protein kinase) can overcome radioresistance in lung cancer. Inhibiting S6K1 sensitizes cancer cells to radiation by downregulating STAT3 signaling, offering a new therapeutic strategy.

Keywords:
S6KSTAT3lung cancerradiation resistance

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Area of Science:

  • Oncology
  • Molecular Biology
  • Radiotherapy Research

Background:

  • Radiotherapy is crucial for locally advanced lung cancer but faces challenges from intrinsic and acquired radioresistance.
  • The serine/threonine kinase S6K1 is implicated in cell survival under stress and is elevated in tumors, yet its precise role in radioresistance is unclear.

Purpose of the Study:

  • To investigate the role of S6K1 in lung cancer radioresistance.
  • To elucidate the underlying molecular mechanisms connecting S6K1 to radiation resistance.

Main Methods:

  • Utilized pharmacologic inhibition and genetic deletion of S6K1 in lung cancer cells.
  • Performed in vitro and in vivo radiosensitivity assays.
  • Conducted transcriptomic analysis to identify downstream targets of S6K1.
  • Assessed STAT3 phosphorylation and transcriptional activity.

Main Results:

  • Increased S6K1 activation correlated with intrinsic radioresistance in lung cancer cells.
  • S6K1 inhibition or deletion significantly enhanced radiosensitivity in vitro and in vivo.
  • S6K1 deletion led to significant downregulation of STAT3 expression and activity.
  • Radiation or active S6K1 restored STAT3 activation in S6K1-deficient cells, confirming S6K1's regulatory role.

Conclusions:

  • A novel S6K1-STAT3 signaling axis drives radioresistance in lung cancer.
  • Targeting S6K1 represents a promising strategy to enhance radiotherapy efficacy in lung cancer patients.