Document Type

Article

Publication Date

2-17-2026

Comments

This article is the author's final published version in International Journal of Molecular Sciences, Volume 27, Issue 4, February 2026, Article Number 1915.

The published version is available at https://doi.org/10.3390/ijms27041915. Copyright © 2026 By The Authors.

Abstract

Radiotherapy is a mainstay in the management of locally advanced lung cancer; however, intrinsic and acquired radioresistance contribute to poor prognosis. S6K1, a serine/threonine kinase, regulates cell growth, protein synthesis, and survival, and is increased in tumors, which is linked to enhanced survival under therapeutic stress, including radiation. The mechanisms, however, are not fully understood. This study investigates the role of S6K1 in lung cancer radioresistance and the mechanisms involved. Intrinsic radioresistance in lung cancer cells was associated with increased S6K1 activation. Pharmacologic inhibition or genetic deletion of S6K1 enhanced radiosensitivity both in vitro and in vivo, highlighting the therapeutic potential of targeting S6K1. Transcriptomic analysis revealed that S6K1 deletion significantly downregulated STAT3 expression, a transcription factor that promotes radioresistance. S6K1 deletion reduced STAT3 phosphorylation and transcriptional activity, thereby sensitizing lung cancer to radiation. Additionally, radiation exposure or overexpression of a constitutively active S6K1 isoform restored STAT3 activation in S6K1 knockout cells, underscoring the regulatory role of S6K1 in STAT3 signaling. Together, these findings establish a novel S6K1-STAT3 axis that drives radioresistance in lung cancer and suggest that targeting this pathway may enhance radiotherapy efficacy.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

41752050

Language

English

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