{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T18:10:06Z","timestamp":1750875006194,"version":"3.41.0"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Cancers with <jats:italic>TERT<\/jats:italic> promoter mutations (TPM) display elevated RAS pathway signaling and mesenchymal traits, and associate with lower patient survival rates. We examined whether RAS pathway signaling in TPM cancers cooperates with mesenchymal features to drive resistance to apoptosis. We observed that RAS pathway signaling in TPM cancers inhibited apoptosis by downregulating the pro-apoptotic protein BIM. By using inhibitors of MEK1\/2 kinases, we rescued the ability of TPM cancer cells to undergo apoptosis, which may have implications for targeted therapies. To further capitalize on this rescue, we explored combination treatments to drive apoptotic cell death. Treatment with the pan-BCL2 inhibitor, navitoclax (NX), in combination with MEK inhibition, significantly increased apoptosis, indicating that these cells are capable of undergoing intrinsic apoptosis, with BIM likely playing a critical role. Further, we found that transcriptional reprogramming of the mesenchymal state of TPM cancers using histone deacetylase inhibitors (HDACi) resulted in a synergistic increase in apoptosis, contingent upon BIM de-repression. Notably, the cause of this apoptosis appeared to be independent of DNA damage. The suppression of the mesenchymal transcription factor SNAI2, which has known roles in recruiting HDACs to silence gene expression, amplified apoptosis. Mechanistically, knockdown of SNAI2 impaired the cellular DNA repair leading to elevated basal levels of phosphorylated H2AX. Our findings show that TPM cancers exhibit specific small molecule vulnerabilities, driven by the convergence of RAS-MEK signaling and impaired HDAC regulation dependent on pro-apoptotic BH3-only proteins. Based on our findings, we propose that stratifying cancers based on TPM may identify a subset of tumors that are responsive to innovative combinations of inhibitors targeting these axes.<\/jats:p>","DOI":"10.1371\/journal.pone.0322961","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T17:31:34Z","timestamp":1750872694000},"page":"e0322961","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["SNAI2 cooperates with MEK1\/2 and HDACs to suppress BIM- and BMF-dependent apoptosis in TERT promoter mutant cancers"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8626-8651","authenticated-orcid":true,"given":"Amol","family":"Tandon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0588-1586","authenticated-orcid":true,"given":"Josh Lewis","family":"Stern","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,6,25]]},"reference":[{"issue":"6127","key":"pone.0322961.ref001","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1126\/science.1235122","article-title":"Cancer genome landscapes","volume":"339","author":"B Vogelstein","year":"2013","journal-title":"Science"},{"issue":"4","key":"pone.0322961.ref002","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.cell.2016.12.015","article-title":"Implementing genome-driven oncology","volume":"168","author":"DM Hyman","year":"2017","journal-title":"Cell"},{"issue":"1","key":"pone.0322961.ref003","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.cell.2012.03.003","article-title":"MYC on the path to cancer","volume":"149","author":"CV Dang","year":"2012","journal-title":"Cell"},{"issue":"6892","key":"pone.0322961.ref004","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1038\/nature00766","article-title":"Mutations of the BRAF gene in human cancer","volume":"417","author":"H Davies","year":"2002","journal-title":"Nature"},{"issue":"1","key":"pone.0322961.ref005","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a001008","article-title":"TP53 mutations in human cancers: origins, consequences, and clinical use","volume":"2","author":"M Olivier","year":"2010","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"5670","key":"pone.0322961.ref006","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1126\/science.1096502","article-title":"High frequency of mutations of the PIK3CA gene in human cancers","volume":"304","author":"Y Samuels","year":"2004","journal-title":"Science"},{"issue":"6122","key":"pone.0322961.ref007","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1126\/science.1230062","article-title":"TERT promoter mutations in familial and sporadic melanoma","volume":"339","author":"S Horn","year":"2013","journal-title":"Science"},{"key":"pone.0322961.ref008","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1038\/ncomms3185","article-title":"Frequency of TERT promoter mutations in human cancers","volume":"4","author":"J Vinagre","year":"2013","journal-title":"Nat Commun"},{"issue":"4","key":"pone.0322961.ref009","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1158\/1541-7786.MCR-16-0003","article-title":"Understanding TERT promoter mutations: a common path to immortality","volume":"14","author":"RJA Bell","year":"2016","journal-title":"Mol Cancer Res"},{"key":"pone.0322961.ref010","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.mrrev.2016.11.002","article-title":"TERT promoter mutations in telomere biology","volume":"771","author":"B Heidenreich","year":"2017","journal-title":"Mutat Res Rev Mutat Res"},{"issue":"2","key":"pone.0322961.ref011","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.3892\/ol.2017.6284","article-title":"Mutation of the TERT promoter leads to poor prognosis of patients with non-small cell lung cancer","volume":"14","author":"S-J Jung","year":"2017","journal-title":"Oncol Lett"},{"issue":"11","key":"pone.0322961.ref012","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.3390\/cancers16112032","article-title":"Prognostic impact of TERT promoter mutations in adult-type diffuse gliomas based on WHO2021 criteria","volume":"16","author":"Y Lee","year":"2024","journal-title":"Cancers (Basel)"},{"issue":"5","key":"pone.0322961.ref013","doi-asserted-by":"crossref","DOI":"10.1210\/jc.2013-3734","article-title":"TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas","volume":"99","author":"M Melo","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"7","key":"pone.0322961.ref014","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1158\/1541-7786.MCR-19-1244","article-title":"Mesenchymal and MAPK expression signatures associate with telomerase promoter mutations in multiple cancers","volume":"18","author":"JL Stern","year":"2020","journal-title":"Mol Cancer Res"},{"issue":"1","key":"pone.0322961.ref015","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1517\/14728222.2011.645805","article-title":"Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy","volume":"16","author":"L Santarpia","year":"2012","journal-title":"Expert Opin Ther Targets"},{"key":"pone.0322961.ref016","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.pharmthera.2018.09.007","article-title":"Hybrid epithelial\/mesenchymal phenotypes promote metastasis and therapy resistance across carcinomas","volume":"194","author":"MK Jolly","year":"2019","journal-title":"Pharmacol Ther"},{"issue":"14","key":"pone.0322961.ref017","doi-asserted-by":"crossref","first-page":"3575","DOI":"10.3390\/cancers13143575","article-title":"HDAC inhibitors: dissecting mechanisms of action to counter tumor heterogeneity","volume":"13","author":"D Karagiannis","year":"2021","journal-title":"Cancers (Basel)"},{"issue":"2","key":"pone.0322961.ref018","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41571-019-0267-4","article-title":"Combining epigenetic drugs with other therapies for solid tumours - past lessons and future promise","volume":"17","author":"D Morel","year":"2020","journal-title":"Nat Rev Clin Oncol"},{"issue":"4","key":"pone.0322961.ref019","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1158\/2159-8290.CD-18-0879","article-title":"MAPK pathway suppression unmasks latent DNA repair defects and confers a chemical synthetic vulnerability in BRAF-, NRAS-, and NF1-mutant melanomas","volume":"9","author":"O Maertens","year":"2019","journal-title":"Cancer Discov"},{"issue":"23","key":"pone.0322961.ref020","doi-asserted-by":"crossref","DOI":"10.1242\/jcs.235127","article-title":"Molecular regulation of Snai2 in development and disease","volume":"132","author":"W Zhou","year":"2019","journal-title":"J Cell Sci"},{"issue":"5443","key":"pone.0322961.ref021","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1126\/science.286.5443.1358","article-title":"Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms","volume":"286","author":"A Bonni","year":"1999","journal-title":"Science"},{"issue":"1","key":"pone.0322961.ref022","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/s41392-023-01705-z","article-title":"Targeting the RAS\/RAF\/MAPK pathway for cancer therapy: from mechanism to clinical studies","volume":"8","author":"ME Bahar","year":"2023","journal-title":"Signal Transduct Target Ther"},{"issue":"1","key":"pone.0322961.ref023","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nrm2308","article-title":"The BCL-2 protein family: opposing activities that mediate cell death","volume":"9","author":"RJ Youle","year":"2008","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"1","key":"pone.0322961.ref024","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrm3722","article-title":"Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy","volume":"15","author":"PE Czabotar","year":"2014","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"9","key":"pone.0322961.ref025","doi-asserted-by":"crossref","first-page":"3421","DOI":"10.1158\/0008-5472.CAN-07-5836","article-title":"ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor","volume":"68","author":"C Tse","year":"2008","journal-title":"Cancer Res"},{"issue":"1","key":"pone.0322961.ref026","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1158\/1078-0432.CCR-17-1577","article-title":"Epithelial-to-mesenchymal transition antagonizes response to targeted therapies in lung cancer by suppressing BIM","volume":"24","author":"K-A Song","year":"2018","journal-title":"Clin Cancer Res"},{"issue":"5","key":"pone.0322961.ref027","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1158\/2159-8290.CD-15-0011","article-title":"The BCL2 family: key mediators of the apoptotic response to targeted anticancer therapeutics","volume":"5","author":"AN Hata","year":"2015","journal-title":"Cancer Discov"},{"issue":"9","key":"pone.0322961.ref028","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1358\/dot.2007.43.9.1112980","article-title":"Vorinostat in cutaneous T-cell lymphoma","volume":"43","author":"M Duvic","year":"2007","journal-title":"Drugs Today (Barc)"},{"issue":"4","key":"pone.0322961.ref029","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/j.cell.2017.07.040","article-title":"Transcription-replication conflicts: orientation matters","volume":"170","author":"Y-L Lin","year":"2017","journal-title":"Cell"},{"issue":"18","key":"pone.0322961.ref030","doi-asserted-by":"crossref","first-page":"13688","DOI":"10.3390\/ijms241813688","article-title":"Glioma stem cells are sensitized to BCL-2 family inhibition by compromising histone deacetylases","volume":"24","author":"A Merati","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"2","key":"pone.0322961.ref031","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2019.06.043","article-title":"Loss of slug compromises DNA damage repair and accelerates stem cell aging in mammary epithelium","volume":"28","author":"KM Gross","year":"2019","journal-title":"Cell Rep"},{"issue":"9","key":"pone.0322961.ref032","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.3390\/genes14091787","article-title":"Enhancing transcriptional reprogramming of mesenchymal glioblastoma with Grainyhead-like 2 and HDAC inhibitors leads to apoptosis and cell-cycle dysregulation","volume":"14","author":"S Kotian","year":"2023","journal-title":"Genes (Basel)"},{"issue":"12","key":"pone.0322961.ref033","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1038\/nrd4281","article-title":"Targeting RAS-ERK signalling in cancer: promises and challenges","volume":"13","author":"AA Samatar","year":"2014","journal-title":"Nat Rev Drug Discov"},{"issue":"11","key":"pone.0322961.ref034","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nrd4389","article-title":"Drugging the undruggable RAS: Mission possible?","volume":"13","author":"AD Cox","year":"2014","journal-title":"Nat Rev Drug Discov"},{"key":"pone.0322961.ref035","doi-asserted-by":"crossref","first-page":"486","DOI":"10.3389\/fcell.2020.00486","article-title":"Histone deacetylase inhibitors to overcome resistance to targeted and immuno therapy in metastatic melanoma","volume":"8","author":"M Yeon","year":"2020","journal-title":"Front Cell Dev Biol"},{"issue":"10","key":"pone.0322961.ref036","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1038\/ng1634","article-title":"The melanocyte differentiation program predisposes to metastasis after neoplastic transformation","volume":"37","author":"PB Gupta","year":"2005","journal-title":"Nat Genet"},{"issue":"7","key":"pone.0322961.ref037","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/nbt.2284","article-title":"Combinatorial drug therapy for cancer in the post-genomic era","volume":"30","author":"B Al-Lazikani","year":"2012","journal-title":"Nat Biotechnol"},{"issue":"2","key":"pone.0322961.ref038","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","article-title":"Drug combination studies and their synergy quantification using the Chou-Talalay method","volume":"70","author":"T-C Chou","year":"2010","journal-title":"Cancer Res"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0322961","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T17:31:48Z","timestamp":1750872708000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0322961"}},"subtitle":[],"editor":[{"given":"Kai","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,6,25]]},"references-count":38,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0322961","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,25]]}}}