@article{4745e91ece4c49afb1e753a2a787a497,
title = "HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non–small cell lung cancer",
abstract = "HDAC3 is one of the main targets of histone deacetylase (HDAC) inhibitors in clinical development as cancer therapies, yet the in vivo role of HDAC3 in solid tumors is unknown. We identified a critical role for HDAC3 in Kras-mutant lung cancer. Using genetically engineered mouse models (GEMMs), we found that HDAC3 is required for lung tumor growth in vivo. HDAC3 was found to direct and enhance the transcription effects of the lung cancer lineage transcription factor NKX2-1 to mediate expression of a common set of target genes. We identified FGFR1 as a critical previously unidentified target of HDAC3. Leveraging this, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as Kras/LKB1-mutant cells develop resistance to the MEK inhibitor trametinib, and this can be reversed by treatment with the HDAC1/HDAC3 inhibitor entinostat. We found that the combination of entinostat plus trametinib treatment elicits therapeutic benefit in the Kras/LKB1 GEMM.",
author = "Eichner, {Lillian J.} and Curtis, {Stephanie D.} and Brun, {Sonja N.} and McGuire, {Caroline K.} and Irena Gushterova and Baumgart, {Joshua T.} and Elijah Trefts and Ross, {Debbie S.} and Rymoff, {Tammy J.} and Shaw, {Reuben J.}",
note = "Funding Information: Acknowledgments:W ethankD.Hargreav es andJ.RemsbergforsupportwithChIP-seqassay development,G.Liangforadviceoninvivoentinostatdosing,andS.Loweforadviceoninvivo trametinibdosing.W ealsothankJ.VanNostr and forconstructivecriticismofthemanuscript. Funding:ThisstudywassupportedbygrantstoR.J.S.fromtheNIH(R35CA220538and P01CA120964)andTheLeonaM.andHarryB.HelmsleyCharitableTrus tgrant#2012-PG-MED002.L.J.E.wassupportedbyapostdoctoralfellowshipfromtheAmericanCancerSociety (PF-15-037-01-DMC), and research reported in this publication was supported by the National CancerInstitute(NCI)oftheNIHunderawardnumberK22CA251636.Thecontentissolelythe responsibility of the authors and does not necessarily represent the official views of the NIH. S.N.BwassupportedbyNCItraininggrant5T32CA009370totheSalkInstituteCancerCenter andNCI5F32CA206400.ThisworkwassupportedbytheNGSandtheRazaviNewman IntegrativeGenomicsandBioinformaticsCoreFa cilities oftheSalkInstitutewithfundingfrom theNIH-NCICCSG:P30014195,theChapmanFoundation,andtheHelmsleyCharitableTrust. TissueT echnology SharedResourceissupportedbyanNCICancerCenterSupportGrant(CCSG P30CA23100).Authorcontributions:L.J.Edesignedallexperiments,performedall experimentsexceptasnotedhere,andwrotethepaper.S.D.C.,S.N.B,andJ.T .B. assistedwith cloningandK Ocelllinegenerationandvalidation.S.N.B.andJ.T .B. assistedwithinvivodrug dosingstudies.S.D.C.assistedwithqRT-PCR.D.S.R.assistedwithanimalhusbandry.T .J.R. assistedwithgenotyping,BLIimaging,andinvivodrugdosing.E.T .assistedwithinvivodrug dosing.C.K.M.performedcellcultureexperiments,W este rnblotanalysis,andqRT-PCRforfig. S4(AtoH).I.G.generatedcelllinesusedforfig.S4(DandE).L.J.E.andR.J.S.conceivedthe project,andR.J.S.supervisedtheprojectandwroteandeditedthepaper.Competing interests:Theauthorsdeclarethattheyhav enocompetinginterests.Dataandmaterials availability:Alldataneededtoevaluatetheconclusionsinthepaperarepresentinthepaper and/orSupplementaryMaterials.RNA-seqandChIP-seqdatahavebeendepositedtotheGene Expression Omnibus (GEO) data repository with accession number GSE164759. Previously published sequencing datathat were reanalyzed here is available under the GEO accession codeGSE36473.Sourcedataareprovidedforallexperiments.Correspondenceandrequestsfor materialsshouldbeaddressedtoR.J.S.orL.J.E. Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.",
year = "2023",
month = mar,
doi = "10.1126/sciadv.add3243",
language = "English (US)",
volume = "9",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "11",
}
