Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities
Kras-driven non-small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice with ortho...
Uložené v:
| Vydané v: | The Journal of experimental medicine Ročník 215; číslo 12; s. 3115 |
|---|---|
| Hlavní autori: | , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
| Vydavateľské údaje: |
United States
03.12.2018
|
| ISSN: | 1540-9538, 1540-9538 |
| On-line prístup: | Zistit podrobnosti o prístupe |
| Tagy: |
Pridať tag
Žiadne tagy, Buďte prvý, kto otaguje tento záznam!
|
| Abstract | Kras-driven non-small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice with orthotopic Kras-driven NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-κB and genes residing in PRC2-regulated chromatin. During this process, tumor cells overcome GSK126 antiproliferative effects. We identified oncogenes that may mediate progression through an in vivo RNAi screen aimed at targets of PRC2/NF-κB. An in vitro compound screening linked GSK126-driven inflammation and therapeutic vulnerability in human cells to regulation of RNA synthesis and proteostasis. Interestingly, GSK126-treated NSCLCs in vivo also showed an enhanced response to a combination of nimesulide and bortezomib. Thus, Ezh2 inhibition may restrict cell proliferation and promote defined adaptive responses. Targeting these responses potentially improves outcomes in Kras-driven NSCLCs. |
|---|---|
| AbstractList | Kras-driven non-small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice with orthotopic Kras-driven NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-κB and genes residing in PRC2-regulated chromatin. During this process, tumor cells overcome GSK126 antiproliferative effects. We identified oncogenes that may mediate progression through an in vivo RNAi screen aimed at targets of PRC2/NF-κB. An in vitro compound screening linked GSK126-driven inflammation and therapeutic vulnerability in human cells to regulation of RNA synthesis and proteostasis. Interestingly, GSK126-treated NSCLCs in vivo also showed an enhanced response to a combination of nimesulide and bortezomib. Thus, Ezh2 inhibition may restrict cell proliferation and promote defined adaptive responses. Targeting these responses potentially improves outcomes in Kras-driven NSCLCs. Kras-driven non-small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice with orthotopic Kras-driven NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-κB and genes residing in PRC2-regulated chromatin. During this process, tumor cells overcome GSK126 antiproliferative effects. We identified oncogenes that may mediate progression through an in vivo RNAi screen aimed at targets of PRC2/NF-κB. An in vitro compound screening linked GSK126-driven inflammation and therapeutic vulnerability in human cells to regulation of RNA synthesis and proteostasis. Interestingly, GSK126-treated NSCLCs in vivo also showed an enhanced response to a combination of nimesulide and bortezomib. Thus, Ezh2 inhibition may restrict cell proliferation and promote defined adaptive responses. Targeting these responses potentially improves outcomes in Kras-driven NSCLCs.Kras-driven non-small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice with orthotopic Kras-driven NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-κB and genes residing in PRC2-regulated chromatin. During this process, tumor cells overcome GSK126 antiproliferative effects. We identified oncogenes that may mediate progression through an in vivo RNAi screen aimed at targets of PRC2/NF-κB. An in vitro compound screening linked GSK126-driven inflammation and therapeutic vulnerability in human cells to regulation of RNA synthesis and proteostasis. Interestingly, GSK126-treated NSCLCs in vivo also showed an enhanced response to a combination of nimesulide and bortezomib. Thus, Ezh2 inhibition may restrict cell proliferation and promote defined adaptive responses. Targeting these responses potentially improves outcomes in Kras-driven NSCLCs. |
| Author | van Lohuizen, Maarten Morris, Ben Gargiulo, Gaetano Hulsman, Danielle Proost, Natalie Schmitt, Matthias J Company, Carlos Siteur, Bjorn Cesaroni, Matteo Beijersbergen, Roderick L Serresi, Michela Lieftink, Cor |
| Author_xml | – sequence: 1 givenname: Michela surname: Serresi fullname: Serresi, Michela organization: Molecular Oncology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany – sequence: 2 givenname: Bjorn orcidid: 0000-0002-0213-8797 surname: Siteur fullname: Siteur, Bjorn organization: Mouse Cancer Clinic, Netherlands Cancer Institute, Amsterdam, Netherlands – sequence: 3 givenname: Danielle orcidid: 0000-0001-9347-8553 surname: Hulsman fullname: Hulsman, Danielle organization: Oncode Institute, Utrecht, Netherlands – sequence: 4 givenname: Carlos surname: Company fullname: Company, Carlos organization: Molecular Oncology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany – sequence: 5 givenname: Matthias J surname: Schmitt fullname: Schmitt, Matthias J organization: Molecular Oncology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany – sequence: 6 givenname: Cor surname: Lieftink fullname: Lieftink, Cor organization: Division of Molecular Carcinogenesis and Netherlands Cancer Institute Robotics and Screening Center, Netherlands Cancer Institute, Amsterdam, Netherlands – sequence: 7 givenname: Ben surname: Morris fullname: Morris, Ben organization: Division of Molecular Carcinogenesis and Netherlands Cancer Institute Robotics and Screening Center, Netherlands Cancer Institute, Amsterdam, Netherlands – sequence: 8 givenname: Matteo surname: Cesaroni fullname: Cesaroni, Matteo organization: Fels Institute, Temple University School of Medicine, Philadelphia, PA – sequence: 9 givenname: Natalie surname: Proost fullname: Proost, Natalie organization: Mouse Cancer Clinic, Netherlands Cancer Institute, Amsterdam, Netherlands – sequence: 10 givenname: Roderick L surname: Beijersbergen fullname: Beijersbergen, Roderick L organization: Division of Molecular Carcinogenesis and Netherlands Cancer Institute Robotics and Screening Center, Netherlands Cancer Institute, Amsterdam, Netherlands – sequence: 11 givenname: Maarten surname: van Lohuizen fullname: van Lohuizen, Maarten email: m.v.lohuizen@nki.nl organization: Oncode Institute, Utrecht, Netherlands – sequence: 12 givenname: Gaetano orcidid: 0000-0001-5414-4251 surname: Gargiulo fullname: Gargiulo, Gaetano email: gaetano.gargiulo@mdc-berlin.de organization: Molecular Oncology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany gaetano.gargiulo@mdc-berlin.de |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30487290$$D View this record in MEDLINE/PubMed |
| BookMark | eNpNkDtPwzAUhS1URB-wMaOMLCm2Y8f2iKryEJVYYA63zjV15TglTirBr6eCIjGdb_jOGc6UjGIbkZBLRueManGzxWbOKdNUU3ZCJkwKmhtZ6NE_HpNpSltKmRCyPCPjggqtuKET8rb82vDMx41f-9638YDZUwcprzu_x5iFIb5nFqLFLoNmF7zzmA6SC9A08NOAWGeQUms99Fhn-yFE7GDtw2EQ0zk5dRASXhxzRl7vli-Lh3z1fP-4uF3lttCiz5kDo4yrBWigxmqmSie4KSg64NKhrKWunVFAZSGdtqUphWDaFFZJ5YTiM3L9u7vr2o8BU181PlkMASK2Q6o4K4wsS6r4Qb06qsO6wbradb6B7rP6e4V_Azp6Zjg |
| CitedBy_id | crossref_primary_10_1016_j_canlet_2019_01_027 crossref_primary_10_1038_s41419_024_07011_y crossref_primary_10_1371_journal_pcbi_1011095 crossref_primary_10_1016_j_cbpa_2019_11_009 crossref_primary_10_1038_s41388_022_02375_x crossref_primary_10_1016_j_ejmech_2024_116470 crossref_primary_10_1038_s41467_021_27451_w crossref_primary_10_2147_OTT_S245422 crossref_primary_10_2147_COPD_S495581 crossref_primary_10_1016_j_bbagrm_2022_194840 crossref_primary_10_3390_cancers16203507 crossref_primary_10_1038_s41419_021_04407_y crossref_primary_10_3390_ph16030451 crossref_primary_10_1038_s41419_019_1810_z crossref_primary_10_1038_s41467_021_26993_3 crossref_primary_10_1016_j_isci_2025_112143 crossref_primary_10_1016_j_biopha_2023_114313 crossref_primary_10_1158_2159_8290_CD_20_0219 crossref_primary_10_1053_j_seminoncol_2022_06_005 crossref_primary_10_1186_s13046_020_01682_z crossref_primary_10_1038_s41388_023_02824_1 crossref_primary_10_1111_febs_15636 crossref_primary_10_1038_s12276_023_01117_7 crossref_primary_10_1007_s10142_025_01563_8 crossref_primary_10_1016_j_jgg_2021_03_013 crossref_primary_10_1084_jem_20240765 crossref_primary_10_1002_advs_202105539 crossref_primary_10_1038_s41467_023_35784_x |
| ContentType | Journal Article |
| Copyright | 2018 Serresi et al. |
| Copyright_xml | – notice: 2018 Serresi et al. |
| DBID | NPM 7X8 |
| DOI | 10.1084/jem.20180801 |
| DatabaseName | PubMed MEDLINE - Academic |
| DatabaseTitle | PubMed MEDLINE - Academic |
| DatabaseTitleList | PubMed MEDLINE - Academic |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | no_fulltext_linktorsrc |
| Discipline | Medicine |
| EISSN | 1540-9538 |
| ExternalDocumentID | 30487290 |
| Genre | Research Support, Non-U.S. Gov't Journal Article |
| GroupedDBID | --- -~X 18M 29K 2WC 36B 4.4 53G 5GY 5RE 5VS ABOCM ABZEH ACGFO ACNCT ACPRK ADBBV AENEX AFOSN AFRAH ALMA_UNASSIGNED_HOLDINGS AOIJS BAWUL BTFSW C45 CS3 D-I DIK DU5 E3Z EBS EJD EMB F5P F9R FRP GX1 H13 HYE IH2 K-O KQ8 L7B N9A NPM O5R O5S OK1 P2P P6G R.V RHF RHI RPM SJN TR2 TRP UHB W8F WOQ 7X8 |
| ID | FETCH-LOGICAL-c384t-1fa979fd4a8a09c8176f42930efa25fe5d58df97a0535f8c696441893c757f472 |
| IEDL.DBID | 7X8 |
| ISICitedReferencesCount | 33 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000451920600016&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 1540-9538 |
| IngestDate | Fri Sep 05 12:30:33 EDT 2025 Wed Feb 19 02:32:51 EST 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 12 |
| Language | English |
| License | 2018 Serresi et al. |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c384t-1fa979fd4a8a09c8176f42930efa25fe5d58df97a0535f8c696441893c757f472 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ORCID | 0000-0001-5414-4251 0000-0002-0213-8797 0000-0001-9347-8553 |
| OpenAccessLink | https://pubmed.ncbi.nlm.nih.gov/PMC6279402 |
| PMID | 30487290 |
| PQID | 2139566072 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_2139566072 pubmed_primary_30487290 |
| PublicationCentury | 2000 |
| PublicationDate | 20181203 |
| PublicationDateYYYYMMDD | 2018-12-03 |
| PublicationDate_xml | – month: 12 year: 2018 text: 20181203 day: 3 |
| PublicationDecade | 2010 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States |
| PublicationTitle | The Journal of experimental medicine |
| PublicationTitleAlternate | J Exp Med |
| PublicationYear | 2018 |
| SSID | ssj0014456 |
| Score | 2.4450731 |
| Snippet | Kras-driven non-small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the... |
| SourceID | proquest pubmed |
| SourceType | Aggregation Database Index Database |
| StartPage | 3115 |
| Title | Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/30487290 https://www.proquest.com/docview/2139566072 |
| Volume | 215 |
| WOSCitedRecordID | wos000451920600016&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1La8MwDDbbOsYuez-6Fx7sapqHE8enMUbLYLT0sEFvmeIH7Shpl7Q97NdPTlJ6Ggx2CYbYIdiS_MmS9RHyABkHGwIwpcEyHgmfZaEJmVSolZn0MoCabEIMBsloJIfNgVvZpFWubWJlqPVMuTPyToBQBaGHJ4LH-RdzrFEuutpQaGyTVojvnVSL0SaKwHnF3uq74L9EzW4S372Edz6Nu4buu6qK_u_gstpkeof__b0jctDAS_pUy8Mx2TL5CdnrNwH0U_LR_R4HdJKPJ1mVq4VN-lpAyXThzB6dou5T5SShoOCSzS160tjJouDUlxwp5JpCs6hG09Vy6gpXVzm22PeMvPe6b88vrCFZYCpM-IL5FqSQVnNIwJMq8UVscY8KPWMhiKyJdJRoKwW4QjA2UbF0CApRjhKRsFwE52Qnn-XmklCAyKDDKXwcxbWj8Ihj9ChRw2Ob4Nfb5H49dykKsYtMQG5myzLdzF6bXNQLkM7rahtpiDYGPQDv6g-jr8m-W9Qq3SS8IS2LKmxuya5aLSZlcVdJBz4Hw_4P0pbFdQ |
| linkProvider | ProQuest |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Ezh2+inhibition+in+Kras-driven+lung+cancer+amplifies+inflammation+and+associated+vulnerabilities&rft.jtitle=The+Journal+of+experimental+medicine&rft.au=Serresi%2C+Michela&rft.au=Siteur%2C+Bjorn&rft.au=Hulsman%2C+Danielle&rft.au=Company%2C+Carlos&rft.date=2018-12-03&rft.eissn=1540-9538&rft.volume=215&rft.issue=12&rft.spage=3115&rft_id=info:doi/10.1084%2Fjem.20180801&rft_id=info%3Apmid%2F30487290&rft_id=info%3Apmid%2F30487290&rft.externalDocID=30487290 |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1540-9538&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1540-9538&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1540-9538&client=summon |