Oncogenic RIT1 mutations confer ferroptosis vulnerability in lung adenocarcinoma
Abstract Members from the RAS GTPase superfamily have been closely implicated in the tumorigenesis of various human cancers. Recent sequencing analysis of lung adenocarcinoma has revealed the prevalence of alterations in the RIT1 gene that is a close RAS paralog. However, relative to RAS subfamily m...
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2025-02-01
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| Series: | Biology Direct |
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| Online Access: | https://doi.org/10.1186/s13062-025-00613-2 |
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| author | Ruilan Ma Dian Yang Peng Wang Ziyi Zhang Xuehong Zhang Jialiang Song Han Liu Shuyan Liu Yingqiu Zhang Lijuan Zou |
| author_facet | Ruilan Ma Dian Yang Peng Wang Ziyi Zhang Xuehong Zhang Jialiang Song Han Liu Shuyan Liu Yingqiu Zhang Lijuan Zou |
| author_sort | Ruilan Ma |
| collection | DOAJ |
| description | Abstract Members from the RAS GTPase superfamily have been closely implicated in the tumorigenesis of various human cancers. Recent sequencing analysis of lung adenocarcinoma has revealed the prevalence of alterations in the RIT1 gene that is a close RAS paralog. However, relative to RAS subfamily members KRAS, NRAS, and HRAS, our characterization of RIT1 oncogenic properties remains incomplete. Therefore, further investigation on RIT1 will facilitate future development of targeted therapies. Our bioinformatic analysis revealed that RIT1 alterations in lung cancer predicted poor survivals but differed from its RAS paralogs by showing largely amplification and mutation. Through biochemical characterization of RIT1 hotspot mutations, we propose that RIT1 alterations were associated with increased protein abundance that promoted cell growth. Transcriptomic profiling indicated that oncogenic RIT1 mutant expression influenced common tumorigenic RAS/MAPK, PI3K/AKT, and E2F1 pathways, in addition to altered NFE2L2 target expression. Importantly, RIT1 mutants markedly sensitized cells to ferroptosis induction, and RIT1 knockdown suppressed ferroptotic cell death. Lung adenocarcinoma NCI-H2110 cells containing endogenous RIT1 M90I mutation were susceptible to ferroptosis induction both in vitro and in vivo within xenograft models. Hence, our study unravels a novel aspect of RIT1 mutations in lung cancer and suggests ferroptosis induction as a potential therapeutic strategy to treat lung cancer patients carrying RIT1 mutations. |
| format | Article |
| id | doaj-art-c00a2e798b0d46a4a3955ca3beed526d |
| institution | Kabale University |
| issn | 1745-6150 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
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| series | Biology Direct |
| spelling | doaj-art-c00a2e798b0d46a4a3955ca3beed526d2025-02-09T12:16:40ZengBMCBiology Direct1745-61502025-02-0120111410.1186/s13062-025-00613-2Oncogenic RIT1 mutations confer ferroptosis vulnerability in lung adenocarcinomaRuilan Ma0Dian Yang1Peng Wang2Ziyi Zhang3Xuehong Zhang4Jialiang Song5Han Liu6Shuyan Liu7Yingqiu Zhang8Lijuan Zou9Department of Radiation Oncology, Second Affiliated Hospital, Dalian Medical UniversityThe Institute of Cancer Stem Cell, Dalian Medical UniversityThe Institute of Cancer Stem Cell, Dalian Medical UniversityThe Institute of Cancer Stem Cell, Dalian Medical UniversityThe Institute of Cancer Stem Cell, Dalian Medical UniversityThe Institute of Cancer Stem Cell, Dalian Medical UniversityThe Institute of Cancer Stem Cell, Dalian Medical UniversityThe Institute of Cancer Stem Cell, Dalian Medical UniversityThe Institute of Cancer Stem Cell, Dalian Medical UniversityDepartment of Radiation Oncology, Second Affiliated Hospital, Dalian Medical UniversityAbstract Members from the RAS GTPase superfamily have been closely implicated in the tumorigenesis of various human cancers. Recent sequencing analysis of lung adenocarcinoma has revealed the prevalence of alterations in the RIT1 gene that is a close RAS paralog. However, relative to RAS subfamily members KRAS, NRAS, and HRAS, our characterization of RIT1 oncogenic properties remains incomplete. Therefore, further investigation on RIT1 will facilitate future development of targeted therapies. Our bioinformatic analysis revealed that RIT1 alterations in lung cancer predicted poor survivals but differed from its RAS paralogs by showing largely amplification and mutation. Through biochemical characterization of RIT1 hotspot mutations, we propose that RIT1 alterations were associated with increased protein abundance that promoted cell growth. Transcriptomic profiling indicated that oncogenic RIT1 mutant expression influenced common tumorigenic RAS/MAPK, PI3K/AKT, and E2F1 pathways, in addition to altered NFE2L2 target expression. Importantly, RIT1 mutants markedly sensitized cells to ferroptosis induction, and RIT1 knockdown suppressed ferroptotic cell death. Lung adenocarcinoma NCI-H2110 cells containing endogenous RIT1 M90I mutation were susceptible to ferroptosis induction both in vitro and in vivo within xenograft models. Hence, our study unravels a novel aspect of RIT1 mutations in lung cancer and suggests ferroptosis induction as a potential therapeutic strategy to treat lung cancer patients carrying RIT1 mutations.https://doi.org/10.1186/s13062-025-00613-2Lung adenocarcinomaRAS familyRIT1GTPaseFerroptosisOncogenic mutation |
| spellingShingle | Ruilan Ma Dian Yang Peng Wang Ziyi Zhang Xuehong Zhang Jialiang Song Han Liu Shuyan Liu Yingqiu Zhang Lijuan Zou Oncogenic RIT1 mutations confer ferroptosis vulnerability in lung adenocarcinoma Biology Direct Lung adenocarcinoma RAS family RIT1 GTPase Ferroptosis Oncogenic mutation |
| title | Oncogenic RIT1 mutations confer ferroptosis vulnerability in lung adenocarcinoma |
| title_full | Oncogenic RIT1 mutations confer ferroptosis vulnerability in lung adenocarcinoma |
| title_fullStr | Oncogenic RIT1 mutations confer ferroptosis vulnerability in lung adenocarcinoma |
| title_full_unstemmed | Oncogenic RIT1 mutations confer ferroptosis vulnerability in lung adenocarcinoma |
| title_short | Oncogenic RIT1 mutations confer ferroptosis vulnerability in lung adenocarcinoma |
| title_sort | oncogenic rit1 mutations confer ferroptosis vulnerability in lung adenocarcinoma |
| topic | Lung adenocarcinoma RAS family RIT1 GTPase Ferroptosis Oncogenic mutation |
| url | https://doi.org/10.1186/s13062-025-00613-2 |
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