Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRAS G12C inhibitor resistant tumors
The clinical success of KRAS inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRAS mutant canc...
Gespeichert in:
| Veröffentlicht in: | Redox biology 2024-12, Vol.78, p.103419 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | |
|---|---|
| container_issue | |
| container_start_page | 103419 |
| container_title | Redox biology |
| container_volume | 78 |
| creator | Wang, Kai Zhang, Xin Fan, Yufei Zhou, Liang Duan, Yajun Li, Su Sun, Zhongkan Zhang, Chunqian Yang, Haoyu Yuan, Wenxiu Peng, Linyuan Ma, Xiaoyu Xiang, Siliang Wang, Tianzhi Yang, Mei Zhang, Zhenyuan Wang, Jiaxuan Wang, Zhongyuan Qian, Minxian |
| description | The clinical success of KRAS
inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRAS
mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRAS
-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers. |
| doi_str_mv | 10.1016/j.redox.2024.103419 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed</sourceid><recordid>TN_cdi_pubmed_primary_39527862</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>39527862</sourcerecordid><originalsourceid>FETCH-pubmed_primary_395278623</originalsourceid><addsrcrecordid>eNqFTk1LAzEUDILYov0Fgrw_sGvysrbbYyl-QBGl7aG3krZZ-oqbLHmv6v57c9Czc5hhhhkYpW6NLo024_tTmfwhfpeoscqJrcz0Qg0RjS3QmslAjZhPOqOuKzT6Sg3s9AEn9RiHipbe7YU-nVAMEBt4nb0vitXbBqFzcvxyPexjaHxiyJRiJ5GJgX1gyjOSHijAYjlbwbPBeTZH2pHEBMnnorggIOc2Jr5Rl437YD_61Wt19_S4nr8U3XnX-sO2S9S61G__vtl_Cz9If0x0</addsrcrecordid><sourcetype>Index Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRAS G12C inhibitor resistant tumors</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>PubMed Central</source><source>EZB Electronic Journals Library</source><creator>Wang, Kai ; Zhang, Xin ; Fan, Yufei ; Zhou, Liang ; Duan, Yajun ; Li, Su ; Sun, Zhongkan ; Zhang, Chunqian ; Yang, Haoyu ; Yuan, Wenxiu ; Peng, Linyuan ; Ma, Xiaoyu ; Xiang, Siliang ; Wang, Tianzhi ; Yang, Mei ; Zhang, Zhenyuan ; Wang, Jiaxuan ; Wang, Zhongyuan ; Qian, Minxian</creator><creatorcontrib>Wang, Kai ; Zhang, Xin ; Fan, Yufei ; Zhou, Liang ; Duan, Yajun ; Li, Su ; Sun, Zhongkan ; Zhang, Chunqian ; Yang, Haoyu ; Yuan, Wenxiu ; Peng, Linyuan ; Ma, Xiaoyu ; Xiang, Siliang ; Wang, Tianzhi ; Yang, Mei ; Zhang, Zhenyuan ; Wang, Jiaxuan ; Wang, Zhongyuan ; Qian, Minxian</creatorcontrib><description>The clinical success of KRAS
inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRAS
mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRAS
-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.</description><identifier>EISSN: 2213-2317</identifier><identifier>DOI: 10.1016/j.redox.2024.103419</identifier><identifier>PMID: 39527862</identifier><language>eng</language><publisher>Netherlands</publisher><subject>Amino Acid Transport System y+ - genetics ; Amino Acid Transport System y+ - metabolism ; Animals ; Antineoplastic Agents - pharmacology ; Cell Line, Tumor ; Drug Resistance, Neoplasm - genetics ; Ferroptosis - drug effects ; Ferroptosis - genetics ; Humans ; MAP Kinase Signaling System - drug effects ; Mice ; Neoplasms - drug therapy ; Neoplasms - genetics ; Neoplasms - metabolism ; Neoplasms - pathology ; Proto-Oncogene Proteins p21(ras) - genetics ; Proto-Oncogene Proteins p21(ras) - metabolism ; SOXB1 Transcription Factors - genetics ; SOXB1 Transcription Factors - metabolism ; Xenograft Model Antitumor Assays</subject><ispartof>Redox biology, 2024-12, Vol.78, p.103419</ispartof><rights>Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,860,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39527862$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Kai</creatorcontrib><creatorcontrib>Zhang, Xin</creatorcontrib><creatorcontrib>Fan, Yufei</creatorcontrib><creatorcontrib>Zhou, Liang</creatorcontrib><creatorcontrib>Duan, Yajun</creatorcontrib><creatorcontrib>Li, Su</creatorcontrib><creatorcontrib>Sun, Zhongkan</creatorcontrib><creatorcontrib>Zhang, Chunqian</creatorcontrib><creatorcontrib>Yang, Haoyu</creatorcontrib><creatorcontrib>Yuan, Wenxiu</creatorcontrib><creatorcontrib>Peng, Linyuan</creatorcontrib><creatorcontrib>Ma, Xiaoyu</creatorcontrib><creatorcontrib>Xiang, Siliang</creatorcontrib><creatorcontrib>Wang, Tianzhi</creatorcontrib><creatorcontrib>Yang, Mei</creatorcontrib><creatorcontrib>Zhang, Zhenyuan</creatorcontrib><creatorcontrib>Wang, Jiaxuan</creatorcontrib><creatorcontrib>Wang, Zhongyuan</creatorcontrib><creatorcontrib>Qian, Minxian</creatorcontrib><title>Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRAS G12C inhibitor resistant tumors</title><title>Redox biology</title><addtitle>Redox Biol</addtitle><description>The clinical success of KRAS
inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRAS
mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRAS
-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.</description><subject>Amino Acid Transport System y+ - genetics</subject><subject>Amino Acid Transport System y+ - metabolism</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Ferroptosis - drug effects</subject><subject>Ferroptosis - genetics</subject><subject>Humans</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Mice</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - genetics</subject><subject>Neoplasms - metabolism</subject><subject>Neoplasms - pathology</subject><subject>Proto-Oncogene Proteins p21(ras) - genetics</subject><subject>Proto-Oncogene Proteins p21(ras) - metabolism</subject><subject>SOXB1 Transcription Factors - genetics</subject><subject>SOXB1 Transcription Factors - metabolism</subject><subject>Xenograft Model Antitumor Assays</subject><issn>2213-2317</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFTk1LAzEUDILYov0Fgrw_sGvysrbbYyl-QBGl7aG3krZZ-oqbLHmv6v57c9Czc5hhhhkYpW6NLo024_tTmfwhfpeoscqJrcz0Qg0RjS3QmslAjZhPOqOuKzT6Sg3s9AEn9RiHipbe7YU-nVAMEBt4nb0vitXbBqFzcvxyPexjaHxiyJRiJ5GJgX1gyjOSHijAYjlbwbPBeTZH2pHEBMnnorggIOc2Jr5Rl437YD_61Wt19_S4nr8U3XnX-sO2S9S61G__vtl_Cz9If0x0</recordid><startdate>202412</startdate><enddate>202412</enddate><creator>Wang, Kai</creator><creator>Zhang, Xin</creator><creator>Fan, Yufei</creator><creator>Zhou, Liang</creator><creator>Duan, Yajun</creator><creator>Li, Su</creator><creator>Sun, Zhongkan</creator><creator>Zhang, Chunqian</creator><creator>Yang, Haoyu</creator><creator>Yuan, Wenxiu</creator><creator>Peng, Linyuan</creator><creator>Ma, Xiaoyu</creator><creator>Xiang, Siliang</creator><creator>Wang, Tianzhi</creator><creator>Yang, Mei</creator><creator>Zhang, Zhenyuan</creator><creator>Wang, Jiaxuan</creator><creator>Wang, Zhongyuan</creator><creator>Qian, Minxian</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>202412</creationdate><title>Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRAS G12C inhibitor resistant tumors</title><author>Wang, Kai ; Zhang, Xin ; Fan, Yufei ; Zhou, Liang ; Duan, Yajun ; Li, Su ; Sun, Zhongkan ; Zhang, Chunqian ; Yang, Haoyu ; Yuan, Wenxiu ; Peng, Linyuan ; Ma, Xiaoyu ; Xiang, Siliang ; Wang, Tianzhi ; Yang, Mei ; Zhang, Zhenyuan ; Wang, Jiaxuan ; Wang, Zhongyuan ; Qian, Minxian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_395278623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Amino Acid Transport System y+ - genetics</topic><topic>Amino Acid Transport System y+ - metabolism</topic><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Ferroptosis - drug effects</topic><topic>Ferroptosis - genetics</topic><topic>Humans</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Mice</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - genetics</topic><topic>Neoplasms - metabolism</topic><topic>Neoplasms - pathology</topic><topic>Proto-Oncogene Proteins p21(ras) - genetics</topic><topic>Proto-Oncogene Proteins p21(ras) - metabolism</topic><topic>SOXB1 Transcription Factors - genetics</topic><topic>SOXB1 Transcription Factors - metabolism</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Kai</creatorcontrib><creatorcontrib>Zhang, Xin</creatorcontrib><creatorcontrib>Fan, Yufei</creatorcontrib><creatorcontrib>Zhou, Liang</creatorcontrib><creatorcontrib>Duan, Yajun</creatorcontrib><creatorcontrib>Li, Su</creatorcontrib><creatorcontrib>Sun, Zhongkan</creatorcontrib><creatorcontrib>Zhang, Chunqian</creatorcontrib><creatorcontrib>Yang, Haoyu</creatorcontrib><creatorcontrib>Yuan, Wenxiu</creatorcontrib><creatorcontrib>Peng, Linyuan</creatorcontrib><creatorcontrib>Ma, Xiaoyu</creatorcontrib><creatorcontrib>Xiang, Siliang</creatorcontrib><creatorcontrib>Wang, Tianzhi</creatorcontrib><creatorcontrib>Yang, Mei</creatorcontrib><creatorcontrib>Zhang, Zhenyuan</creatorcontrib><creatorcontrib>Wang, Jiaxuan</creatorcontrib><creatorcontrib>Wang, Zhongyuan</creatorcontrib><creatorcontrib>Qian, Minxian</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Redox biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Kai</au><au>Zhang, Xin</au><au>Fan, Yufei</au><au>Zhou, Liang</au><au>Duan, Yajun</au><au>Li, Su</au><au>Sun, Zhongkan</au><au>Zhang, Chunqian</au><au>Yang, Haoyu</au><au>Yuan, Wenxiu</au><au>Peng, Linyuan</au><au>Ma, Xiaoyu</au><au>Xiang, Siliang</au><au>Wang, Tianzhi</au><au>Yang, Mei</au><au>Zhang, Zhenyuan</au><au>Wang, Jiaxuan</au><au>Wang, Zhongyuan</au><au>Qian, Minxian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRAS G12C inhibitor resistant tumors</atitle><jtitle>Redox biology</jtitle><addtitle>Redox Biol</addtitle><date>2024-12</date><risdate>2024</risdate><volume>78</volume><spage>103419</spage><pages>103419-</pages><eissn>2213-2317</eissn><abstract>The clinical success of KRAS
inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance. A novel and effective treatment to revert or target this resistance is urgent. To this end, we established G12Ci (AMG510 and MRTX849) resistant KRAS
mutant cancer cell lines and screened with an FDA-approved drug library. We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells. Mechanistically, the G12Ci resistant cells exhibited reactivation of MAPK signaling, which repressed SOX2-mediated expression of cystine transporter SLC7A11 and iron exporter SLC40A1. Consequently, the low intracellular GSH level but high iron content engendered hypersensitivity of these resistant tumors to ferroptosis inducers. Ectopic overexpression of SOX2 or SLC7A11 and SLC40A1 conferred resistance to ferroptosis in the G12Ci resistant cells. Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRAS
-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.</abstract><cop>Netherlands</cop><pmid>39527862</pmid><doi>10.1016/j.redox.2024.103419</doi></addata></record> |
| fulltext | fulltext |
| identifier | EISSN: 2213-2317 |
| ispartof | Redox biology, 2024-12, Vol.78, p.103419 |
| issn | 2213-2317 |
| language | eng |
| recordid | cdi_pubmed_primary_39527862 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central; EZB Electronic Journals Library |
| subjects | Amino Acid Transport System y+ - genetics Amino Acid Transport System y+ - metabolism Animals Antineoplastic Agents - pharmacology Cell Line, Tumor Drug Resistance, Neoplasm - genetics Ferroptosis - drug effects Ferroptosis - genetics Humans MAP Kinase Signaling System - drug effects Mice Neoplasms - drug therapy Neoplasms - genetics Neoplasms - metabolism Neoplasms - pathology Proto-Oncogene Proteins p21(ras) - genetics Proto-Oncogene Proteins p21(ras) - metabolism SOXB1 Transcription Factors - genetics SOXB1 Transcription Factors - metabolism Xenograft Model Antitumor Assays |
| title | Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRAS G12C inhibitor resistant tumors |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-11T18%3A38%3A40IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Reactivation%20of%20MAPK-SOX2%20pathway%20confers%20ferroptosis%20sensitivity%20in%20KRAS%20G12C%20inhibitor%20resistant%20tumors&rft.jtitle=Redox%20biology&rft.au=Wang,%20Kai&rft.date=2024-12&rft.volume=78&rft.spage=103419&rft.pages=103419-&rft.eissn=2213-2317&rft_id=info:doi/10.1016/j.redox.2024.103419&rft_dat=%3Cpubmed%3E39527862%3C/pubmed%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/39527862&rfr_iscdi=true |