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

## TL;DR

This study shows that S6K1 promotes radioresistance in lung cancer by activating STAT3, suggesting that targeting S6K1 could improve radiotherapy outcomes.

## Contribution

The study identifies a novel S6K1–STAT3 signaling axis that drives radioresistance in lung cancer.

## Key findings

- S6K1 inhibition or deletion increases radiosensitivity in lung cancer cells.
- S6K1 regulates STAT3 phosphorylation and transcriptional activity.
- Targeting S6K1 reduces STAT3 activation and enhances radiation response.

## 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.