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 d...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02300-7 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yen-Han Tseng |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8688c7b1372d401ca7bae3a8b4324685 |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-8688c7b1372d401ca7bae3a8b43246852025-02-02T12:08:53ZengNature Publishing GroupCell Death Discovery2058-77162025-01-0111111510.1038/s41420-025-02300-7Utilizing TP53 hotspot mutations as effective predictors of gemcitabine treatment outcome in non-small-cell lung cancerYen-Han Tseng0Trieu Thi My Tran1Jinghua Tsai Chang2Yu-Tang Huang3Anh Thuc Nguyen4Ian Yi‑Feng Chang5Yi-Tung Chen6Hao-Wen Hsieh7Yue-Li Juang8Peter Mu-Hsin Chang9Tzu-Yi Huang10Ying-Chih Chang11Yuh-Min Chen12Hsuan Liu13Chi-Ying F. Huang14Department of Chest Medicine, Taipei Veterans General HospitalInstitute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung UniversityInstitute of Medicine, Chung Shan Medical UniversityInstitute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung UniversityInstitute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung UniversityTaiwan National Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia SinicaTaiwan National Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia SinicaDepartment of Neurosurgery, Lin-Kou Medical Center, Chang Gung Memorial HospitalInstitute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung UniversitySchool of Medicine, National Yang Ming Chiao Tung UniversityProgram in Molecular Medicine, School of Life Sciences, National Yang Ming Chiao Tung UniversityGenomics Research Center, Academia SinicaDepartment of Chest Medicine, Taipei Veterans General HospitalBiomedical Industry Ph.D. Program, National Yang Ming Chiao Tung UniversityInstitute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung UniversityAbstract 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.https://doi.org/10.1038/s41420-025-02300-7 |
| spellingShingle | 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 Utilizing TP53 hotspot mutations as effective predictors of gemcitabine treatment outcome in non-small-cell lung cancer Cell Death Discovery |
| title | Utilizing TP53 hotspot mutations as effective predictors of gemcitabine treatment outcome in non-small-cell lung cancer |
| title_full | Utilizing TP53 hotspot mutations as effective predictors of gemcitabine treatment outcome in non-small-cell lung cancer |
| title_fullStr | Utilizing TP53 hotspot mutations as effective predictors of gemcitabine treatment outcome in non-small-cell lung cancer |
| title_full_unstemmed | Utilizing TP53 hotspot mutations as effective predictors of gemcitabine treatment outcome in non-small-cell lung cancer |
| title_short | Utilizing TP53 hotspot mutations as effective predictors of gemcitabine treatment outcome in non-small-cell lung cancer |
| title_sort | utilizing tp53 hotspot mutations as effective predictors of gemcitabine treatment outcome in non small cell lung cancer |
| url | https://doi.org/10.1038/s41420-025-02300-7 |
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