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

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

doi:10.1038/s41420-025-02300-7

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

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^*

^*Corresponding author for this work

Department of Molecular Biology

Research output: Contribution to journal › Journal Article › peer-review

7 Scopus citations

Abstract

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.

Original language	English
Article number	26
Pages (from-to)	26
Journal	Cell Death Discovery
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41420-025-02300-7
State	Published - 27 01 2025

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Tseng, Y. H., Tran, T. T. M., Tsai Chang, J., Huang, Y. T., Nguyen, A. T., Chang, I. YF., Chen, Y. T., Hsieh, H. W., Juang, Y. L., Chang, P. M. H., Huang, T. Y., Chang, Y. C., Chen, Y. M., Liu, H., & Huang, C. Y. F. (2025). Utilizing TP53 hotspot mutations as effective predictors of gemcitabine treatment outcome in non-small-cell lung cancer. Cell Death Discovery, 11(1), 26. Article 26. https://doi.org/10.1038/s41420-025-02300-7

@article{675f55ab6dc04201847c4c49c31c6820,

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

abstract = "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.",

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

note = "{\textcopyright} 2025. The Author(s).",

year = "2025",

month = jan,

day = "27",

doi = "10.1038/s41420-025-02300-7",

language = "英语",

volume = "11",

pages = "26",

journal = "Cell Death Discovery",

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Tseng, YH, Tran, TTM, Tsai Chang, J, Huang, YT, Nguyen, AT, Chang, IYF, Chen, YT, Hsieh, HW, Juang, YL, Chang, PMH, Huang, TY, Chang, YC, Chen, YM, Liu, H & Huang, CYF 2025, 'Utilizing TP53 hotspot mutations as effective predictors of gemcitabine treatment outcome in non-small-cell lung cancer', Cell Death Discovery, vol. 11, no. 1, 26, pp. 26. https://doi.org/10.1038/s41420-025-02300-7

TY - JOUR

T1 - Utilizing TP53 hotspot mutations as effective predictors of gemcitabine treatment outcome in non-small-cell lung cancer

AU - Tseng, Yen Han

AU - Tran, Trieu Thi My

AU - Tsai Chang, Jinghua

AU - Huang, Yu Tang

AU - Nguyen, Anh Thuc

AU - Chang, Ian Yi‑Feng

AU - Chen, Yi Tung

AU - Hsieh, Hao Wen

AU - Juang, Yue Li

AU - Chang, Peter Mu Hsin

AU - Huang, Tzu Yi

AU - Chang, Ying Chih

AU - Chen, Yuh Min

AU - Liu, Hsuan

AU - Huang, Chi Ying F.

PY - 2025/1/27

Y1 - 2025/1/27

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85218185248

U2 - 10.1038/s41420-025-02300-7

DO - 10.1038/s41420-025-02300-7

M3 - 文章

C2 - 39870629

AN - SCOPUS:85218185248

SN - 2058-7716

VL - 11

SP - 26

JO - Cell Death Discovery

JF - Cell Death Discovery

IS - 1

M1 - 26

ER -

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

Abstract

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