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Background <p>Radiotherapy resistance in lung adenocarcinoma (LUAD) complicates treatment and worsens outcomes. Growing evidence indicates that cancer stemness contributes to radioresistance and poor prognosis. This study aimed to develop a prognostic model based on radioresistant stemness genes and to identify candidate therapeutics.</p> Methods <p>Machine-learning methods were used to identify key radioresistant stemness genes (RRSKGs) and construct a prognostic risk score, the Radioresistant Stemness Risk Prognostic Score (RRSRPS). Its prognostic value was evaluated by Cox regression. PLK1 was prioritized for mechanistic analysis. Single-cell RNA sequencing and immune deconvolution characterized PLK1’s cellular distribution and associations with immune infiltration. Molecular docking and flow cytometry examined the relationship between cisplatin and PLK1. Clonogenic assays and xenograft models assessed whether cisplatin enhances radiosensitivity.</p> Results <p>RRSRPS was an independent prognostic factor. PLK1 was identified as the target through screening. Knockdown of PLK1 significantly suppressed cell viability and enhanced radiosensitivity, increasing apoptosis by 40.06 ± 1.524% versus control. Mechanistic studies showed PLK1 acts via the JAK-STAT3 pathway, confirmed by rescue experiments. Drug sensitivity analysis and molecular docking identified cisplatin as a specific PLK1 inhibitor. Clonogenic and in vivo assays demonstrated that cisplatin combined with radiotherapy synergistically inhibited tumor growth, reducing tumor volume by 697 ± 41.81&#xa0;mm³ compared to control.</p> Conclusions <p>RRSRPS is a robust, independent prognostic indicator in LUAD. Cisplatin increases radiosensitivity, potentially via PLK1-related mechanisms, offering a feasible precision-medicine strategy for patients with radioresistant disease.</p>

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Integration of machine learning-based screening approaches and single-cell sequencing technique to identify cancer stemness genes associated with radiotherapy resistance in lung adenocarcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月4日

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  • Xiao-jia Cui,
  • Bai-xia Yang,
  • Da-ming Hang,
  • Ye Tian,
  • Guo-mei Tai

摘要

Background

Radiotherapy resistance in lung adenocarcinoma (LUAD) complicates treatment and worsens outcomes. Growing evidence indicates that cancer stemness contributes to radioresistance and poor prognosis. This study aimed to develop a prognostic model based on radioresistant stemness genes and to identify candidate therapeutics.

Methods

Machine-learning methods were used to identify key radioresistant stemness genes (RRSKGs) and construct a prognostic risk score, the Radioresistant Stemness Risk Prognostic Score (RRSRPS). Its prognostic value was evaluated by Cox regression. PLK1 was prioritized for mechanistic analysis. Single-cell RNA sequencing and immune deconvolution characterized PLK1’s cellular distribution and associations with immune infiltration. Molecular docking and flow cytometry examined the relationship between cisplatin and PLK1. Clonogenic assays and xenograft models assessed whether cisplatin enhances radiosensitivity.

Results

RRSRPS was an independent prognostic factor. PLK1 was identified as the target through screening. Knockdown of PLK1 significantly suppressed cell viability and enhanced radiosensitivity, increasing apoptosis by 40.06 ± 1.524% versus control. Mechanistic studies showed PLK1 acts via the JAK-STAT3 pathway, confirmed by rescue experiments. Drug sensitivity analysis and molecular docking identified cisplatin as a specific PLK1 inhibitor. Clonogenic and in vivo assays demonstrated that cisplatin combined with radiotherapy synergistically inhibited tumor growth, reducing tumor volume by 697 ± 41.81 mm³ compared to control.

Conclusions

RRSRPS is a robust, independent prognostic indicator in LUAD. Cisplatin increases radiosensitivity, potentially via PLK1-related mechanisms, offering a feasible precision-medicine strategy for patients with radioresistant disease.