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<p><i>TP53</i> mutations are recognized to correlate with a worse prognosis in individuals with non-small cell lung cancer (NSCLC). There exists an immediate necessity to pinpoint selective treatment for patients carrying <i>TP53</i> mutations. Potential drugs were identified by comparing drug sensitivity differences, represented by the half-maximal inhibitory concentration (IC50), between <i>TP53</i> mutant and wild-type NSCLC cell lines using database analysis. In addition, clinical data from NSCLC patients were collected to evaluate both their <i>TP53</i> status and their response to gemcitabine, thereby facilitating further validation. Subsequently, NSCLC cell lines with different <i>TP53</i> status (A549 and H1299) were subjected to gemcitabine treatment to investigate the association between <i>TP53</i> mutations and gemcitabine response. According to the dataset, NSCLC cell lines carrying <i>TP53</i> mutations displayed heightened sensitivity to gemcitabine. From a clinical standpoint, patients exhibiting <i>TP53</i> hotspot mutations demonstrated prolonged overall survival upon gemcitabine treatment. In vitro, overexpressing various hotspot <i>TP53</i> mutations significantly sensitized H1299 cells to gemcitabine. Moreover, the knockdown of <i>TP53</i> in A549 cells notably augmented sensitivity to gemcitabine treatment, as evidenced by cell viability and reproductive cell death assays. Conversely, the overexpression of wild-type <i>TP53</i> in H1299 cells led to an increased resistance against gemcitabine. Gemcitabine is a treatment option for patients with non-small cell lung cancer (NSCLC) who carry <i>TP53</i> hotspot mutations. This potential effectiveness might arise from its ability to disrupt DNA damage repair processes, leading to G2/M phase cell cycle arrest or an augmentation of mitotic abnormalities, eventually cause cell death. As a result, when planning treatment strategies for NSCLC patients possessing <i>TP53</i> hotspot mutations, gemcitabine should be considered to incorporate into the indication.</p>

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Utilizing TP53 hotspot mutations as effective predictors of gemcitabine treatment outcome in non-small-cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月27日

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  • Yen-Han Tseng,
  • Trieu Thi My Tran,
  • Jinghua Tsai Chang,
  • Yu-Tang Huang,
  • Anh Thuc Nguyen,
  • Ian Yi‑Feng Chang,
  • Yi-Tung Chen,
  • Hao-Wen Hsieh,
  • Yue-Li Juang,
  • Peter Mu-Hsin Chang,
  • Tzu-Yi Huang,
  • Ying-Chih Chang,
  • Yuh-Min Chen,
  • Hsuan Liu,
  • Chi-Ying F. Huang

摘要

TP53 mutations are recognized to correlate with a worse prognosis in individuals with non-small cell lung cancer (NSCLC). There exists an immediate necessity to pinpoint selective treatment for patients carrying TP53 mutations. Potential drugs were identified by comparing drug sensitivity differences, represented by the half-maximal inhibitory concentration (IC50), between TP53 mutant and wild-type NSCLC cell lines using database analysis. In addition, clinical data from NSCLC patients were collected to evaluate both their TP53 status and their response to gemcitabine, thereby facilitating further validation. Subsequently, NSCLC cell lines with different TP53 status (A549 and H1299) were subjected to gemcitabine treatment to investigate the association between TP53 mutations and gemcitabine response. According to the dataset, NSCLC cell lines carrying TP53 mutations displayed heightened sensitivity to gemcitabine. From a clinical standpoint, patients exhibiting TP53 hotspot mutations demonstrated prolonged overall survival upon gemcitabine treatment. In vitro, overexpressing various hotspot TP53 mutations significantly sensitized H1299 cells to gemcitabine. Moreover, the knockdown of TP53 in A549 cells notably augmented sensitivity to gemcitabine treatment, as evidenced by cell viability and reproductive cell death assays. Conversely, the overexpression of wild-type TP53 in H1299 cells led to an increased resistance against gemcitabine. Gemcitabine is a treatment option for patients with non-small cell lung cancer (NSCLC) who carry TP53 hotspot mutations. This potential effectiveness might arise from its ability to disrupt DNA damage repair processes, leading to G2/M phase cell cycle arrest or an augmentation of mitotic abnormalities, eventually cause cell death. As a result, when planning treatment strategies for NSCLC patients possessing TP53 hotspot mutations, gemcitabine should be considered to incorporate into the indication.