KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS
The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediate...
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| Veröffentlicht in: | Cell 2018-02, Vol.172 (4), p.857-868.e15 |
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| creator | Ambrogio, Chiara Köhler, Jens Zhou, Zhi-Wei Wang, Haiyun Paranal, Raymond Li, Jiaqi Capelletti, Marzia Caffarra, Cristina Li, Shuai Lv, Qi Gondi, Sudershan Hunter, John C. Lu, Jia Chiarle, Roberto Santamaría, David Westover, Kenneth D. Jänne, Pasi A. |
| description | The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRASD154Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers.
[Display omitted]
•Wild-type KRAS expression affects cellular fitness in KRAS mutant LUAD•Wild-type KRAS expression impairs response to MEK inhibitors in KRAS mutant LUAD•Wild-type KRAS inhibitory effect is dependent on dimerization with mutant KRAS•Blocking mutant KRAS dimerization impairs oncogenic properties in vivo
The tumor-suppressive function of wild-type KRAS depends on its dimerization capacity with mutant KRAS. |
| doi_str_mv | 10.1016/j.cell.2017.12.020 |
| format | Article |
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[Display omitted]
•Wild-type KRAS expression affects cellular fitness in KRAS mutant LUAD•Wild-type KRAS expression impairs response to MEK inhibitors in KRAS mutant LUAD•Wild-type KRAS inhibitory effect is dependent on dimerization with mutant KRAS•Blocking mutant KRAS dimerization impairs oncogenic properties in vivo
The tumor-suppressive function of wild-type KRAS depends on its dimerization capacity with mutant KRAS.</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2017.12.020</identifier><identifier>PMID: 29336889</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenocarcinoma of Lung - drug therapy ; Adenocarcinoma of Lung - enzymology ; Adenocarcinoma of Lung - genetics ; Adenocarcinoma of Lung - pathology ; allelic imbalance ; Amino Acid Substitution ; Animals ; Cell Line, Tumor ; dimerization ; drug resistance ; Enzyme Inhibitors - pharmacology ; HEK293 Cells ; Humans ; KRAS oncogene ; Loss of Heterozygosity ; lung adenocarcinoma ; Lung Neoplasms - drug therapy ; Lung Neoplasms - enzymology ; Lung Neoplasms - genetics ; Lung Neoplasms - pathology ; MAP Kinase Kinase Kinases - antagonists & inhibitors ; MAP Kinase Kinase Kinases - genetics ; MAP Kinase Kinase Kinases - metabolism ; MAPK pathway ; MEK inhibitors ; Mice ; Mice, Knockout ; Mutation, Missense ; Protein Multimerization - drug effects ; Protein Multimerization - genetics ; Proto-Oncogene Proteins p21(ras) - genetics ; Proto-Oncogene Proteins p21(ras) - metabolism ; wild-type allele</subject><ispartof>Cell, 2018-02, Vol.172 (4), p.857-868.e15</ispartof><rights>2017 Elsevier Inc.</rights><rights>Copyright © 2017 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c466t-5876eb83ee146e52d6e883e97f89e0543c6895b907c1b83662618f27e328d7a43</citedby><cites>FETCH-LOGICAL-c466t-5876eb83ee146e52d6e883e97f89e0543c6895b907c1b83662618f27e328d7a43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0092867417315003$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29336889$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ambrogio, Chiara</creatorcontrib><creatorcontrib>Köhler, Jens</creatorcontrib><creatorcontrib>Zhou, Zhi-Wei</creatorcontrib><creatorcontrib>Wang, Haiyun</creatorcontrib><creatorcontrib>Paranal, Raymond</creatorcontrib><creatorcontrib>Li, Jiaqi</creatorcontrib><creatorcontrib>Capelletti, Marzia</creatorcontrib><creatorcontrib>Caffarra, Cristina</creatorcontrib><creatorcontrib>Li, Shuai</creatorcontrib><creatorcontrib>Lv, Qi</creatorcontrib><creatorcontrib>Gondi, Sudershan</creatorcontrib><creatorcontrib>Hunter, John C.</creatorcontrib><creatorcontrib>Lu, Jia</creatorcontrib><creatorcontrib>Chiarle, Roberto</creatorcontrib><creatorcontrib>Santamaría, David</creatorcontrib><creatorcontrib>Westover, Kenneth D.</creatorcontrib><creatorcontrib>Jänne, Pasi A.</creatorcontrib><title>KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS</title><title>Cell</title><addtitle>Cell</addtitle><description>The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRASD154Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers.
[Display omitted]
•Wild-type KRAS expression affects cellular fitness in KRAS mutant LUAD•Wild-type KRAS expression impairs response to MEK inhibitors in KRAS mutant LUAD•Wild-type KRAS inhibitory effect is dependent on dimerization with mutant KRAS•Blocking mutant KRAS dimerization impairs oncogenic properties in vivo
The tumor-suppressive function of wild-type KRAS depends on its dimerization capacity with mutant KRAS.</description><subject>Adenocarcinoma of Lung - drug therapy</subject><subject>Adenocarcinoma of Lung - enzymology</subject><subject>Adenocarcinoma of Lung - genetics</subject><subject>Adenocarcinoma of Lung - pathology</subject><subject>allelic imbalance</subject><subject>Amino Acid Substitution</subject><subject>Animals</subject><subject>Cell Line, Tumor</subject><subject>dimerization</subject><subject>drug resistance</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>KRAS oncogene</subject><subject>Loss of Heterozygosity</subject><subject>lung adenocarcinoma</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - enzymology</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - pathology</subject><subject>MAP Kinase Kinase Kinases - antagonists & inhibitors</subject><subject>MAP Kinase Kinase Kinases - genetics</subject><subject>MAP Kinase Kinase Kinases - metabolism</subject><subject>MAPK pathway</subject><subject>MEK inhibitors</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mutation, Missense</subject><subject>Protein Multimerization - drug effects</subject><subject>Protein Multimerization - genetics</subject><subject>Proto-Oncogene Proteins p21(ras) - genetics</subject><subject>Proto-Oncogene Proteins p21(ras) - metabolism</subject><subject>wild-type allele</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtOwzAQRS0EgvL4ARbISzYJthO_JDYVFKgAIfFYsLJSZwKuGqfYLhJ8PYlaWLIazejcK81B6JiSnBIqzua5hcUiZ4TKnLKcMLKFRpRomZVUsm00IkSzTAlZ7qH9GOeEEMU530V7TBeFUEqP0Ovt4_gJX7oWgvuukus8nrbLyqaI7ye3eOrf3cylLuAn8NEl9-nSF658jR-87d7AO4vHdnPuGny_SpVPeCg9RDtNtYhwtJkH6OVq8nxxk909XE8vxneZLYVIGVdSwEwVALQUwFktQPWblo3SQHhZWKE0n2kiLe0xIZigqmESCqZqWZXFATpd9y5D97GCmEzr4iCm8tCtoqG6zytOKe9RtkZt6GIM0JhlcG0VvgwlZlBq5mZImkGpocz0SvvQyaZ_NWuh_ov8OuyB8zUA_ZefDoKJ1oG3ULsANpm6c__1_wC3wYXv</recordid><startdate>20180208</startdate><enddate>20180208</enddate><creator>Ambrogio, Chiara</creator><creator>Köhler, Jens</creator><creator>Zhou, Zhi-Wei</creator><creator>Wang, Haiyun</creator><creator>Paranal, Raymond</creator><creator>Li, Jiaqi</creator><creator>Capelletti, Marzia</creator><creator>Caffarra, Cristina</creator><creator>Li, Shuai</creator><creator>Lv, Qi</creator><creator>Gondi, Sudershan</creator><creator>Hunter, John C.</creator><creator>Lu, Jia</creator><creator>Chiarle, Roberto</creator><creator>Santamaría, David</creator><creator>Westover, Kenneth D.</creator><creator>Jänne, Pasi A.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20180208</creationdate><title>KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS</title><author>Ambrogio, Chiara ; Köhler, Jens ; Zhou, Zhi-Wei ; Wang, Haiyun ; Paranal, Raymond ; Li, Jiaqi ; Capelletti, Marzia ; Caffarra, Cristina ; Li, Shuai ; Lv, Qi ; Gondi, Sudershan ; Hunter, John C. ; Lu, Jia ; Chiarle, Roberto ; Santamaría, David ; Westover, Kenneth D. ; Jänne, Pasi A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c466t-5876eb83ee146e52d6e883e97f89e0543c6895b907c1b83662618f27e328d7a43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adenocarcinoma of Lung - drug therapy</topic><topic>Adenocarcinoma of Lung - enzymology</topic><topic>Adenocarcinoma of Lung - genetics</topic><topic>Adenocarcinoma of Lung - pathology</topic><topic>allelic imbalance</topic><topic>Amino Acid Substitution</topic><topic>Animals</topic><topic>Cell Line, Tumor</topic><topic>dimerization</topic><topic>drug resistance</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>KRAS oncogene</topic><topic>Loss of Heterozygosity</topic><topic>lung adenocarcinoma</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - enzymology</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - pathology</topic><topic>MAP Kinase Kinase Kinases - antagonists & inhibitors</topic><topic>MAP Kinase Kinase Kinases - genetics</topic><topic>MAP Kinase Kinase Kinases - metabolism</topic><topic>MAPK pathway</topic><topic>MEK inhibitors</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mutation, Missense</topic><topic>Protein Multimerization - drug effects</topic><topic>Protein Multimerization - genetics</topic><topic>Proto-Oncogene Proteins p21(ras) - genetics</topic><topic>Proto-Oncogene Proteins p21(ras) - metabolism</topic><topic>wild-type allele</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ambrogio, Chiara</creatorcontrib><creatorcontrib>Köhler, Jens</creatorcontrib><creatorcontrib>Zhou, Zhi-Wei</creatorcontrib><creatorcontrib>Wang, Haiyun</creatorcontrib><creatorcontrib>Paranal, Raymond</creatorcontrib><creatorcontrib>Li, Jiaqi</creatorcontrib><creatorcontrib>Capelletti, Marzia</creatorcontrib><creatorcontrib>Caffarra, Cristina</creatorcontrib><creatorcontrib>Li, Shuai</creatorcontrib><creatorcontrib>Lv, Qi</creatorcontrib><creatorcontrib>Gondi, Sudershan</creatorcontrib><creatorcontrib>Hunter, John C.</creatorcontrib><creatorcontrib>Lu, Jia</creatorcontrib><creatorcontrib>Chiarle, Roberto</creatorcontrib><creatorcontrib>Santamaría, David</creatorcontrib><creatorcontrib>Westover, Kenneth D.</creatorcontrib><creatorcontrib>Jänne, Pasi A.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ambrogio, Chiara</au><au>Köhler, Jens</au><au>Zhou, Zhi-Wei</au><au>Wang, Haiyun</au><au>Paranal, Raymond</au><au>Li, Jiaqi</au><au>Capelletti, Marzia</au><au>Caffarra, Cristina</au><au>Li, Shuai</au><au>Lv, Qi</au><au>Gondi, Sudershan</au><au>Hunter, John C.</au><au>Lu, Jia</au><au>Chiarle, Roberto</au><au>Santamaría, David</au><au>Westover, Kenneth D.</au><au>Jänne, Pasi A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2018-02-08</date><risdate>2018</risdate><volume>172</volume><issue>4</issue><spage>857</spage><epage>868.e15</epage><pages>857-868.e15</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><abstract>The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRASD154Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers.
[Display omitted]
•Wild-type KRAS expression affects cellular fitness in KRAS mutant LUAD•Wild-type KRAS expression impairs response to MEK inhibitors in KRAS mutant LUAD•Wild-type KRAS inhibitory effect is dependent on dimerization with mutant KRAS•Blocking mutant KRAS dimerization impairs oncogenic properties in vivo
The tumor-suppressive function of wild-type KRAS depends on its dimerization capacity with mutant KRAS.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>29336889</pmid><doi>10.1016/j.cell.2017.12.020</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Adenocarcinoma of Lung - drug therapy Adenocarcinoma of Lung - enzymology Adenocarcinoma of Lung - genetics Adenocarcinoma of Lung - pathology allelic imbalance Amino Acid Substitution Animals Cell Line, Tumor dimerization drug resistance Enzyme Inhibitors - pharmacology HEK293 Cells Humans KRAS oncogene Loss of Heterozygosity lung adenocarcinoma Lung Neoplasms - drug therapy Lung Neoplasms - enzymology Lung Neoplasms - genetics Lung Neoplasms - pathology MAP Kinase Kinase Kinases - antagonists & inhibitors MAP Kinase Kinase Kinases - genetics MAP Kinase Kinase Kinases - metabolism MAPK pathway MEK inhibitors Mice Mice, Knockout Mutation, Missense Protein Multimerization - drug effects Protein Multimerization - genetics Proto-Oncogene Proteins p21(ras) - genetics Proto-Oncogene Proteins p21(ras) - metabolism wild-type allele |
| title | KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS |
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