{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T17:46:06Z","timestamp":1781286366329,"version":"3.54.1"},"reference-count":51,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T00:00:00Z","timestamp":1642723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["NMRC\/STaR\/0021\/2014"],"award-info":[{"award-number":["NMRC\/STaR\/0021\/2014"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["NMRC\/CG\/012\/2013"],"award-info":[{"award-number":["NMRC\/CG\/012\/2013"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001459","name":"Ministry of Education","doi-asserted-by":"publisher","award":["MOE2013-T2-2-150"],"award-info":[{"award-number":["MOE2013-T2-2-150"]}],"id":[{"id":"10.13039\/501100001459","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001459","name":"Ministry of Education","doi-asserted-by":"publisher","award":["MOE2014-T3-1-006"],"award-info":[{"award-number":["MOE2014-T3-1-006"]}],"id":[{"id":"10.13039\/501100001459","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple myeloma (MM) is a hematological disease marked by abnormal growth of B cells in bone marrow. Inherent chromosomal instability and DNA damage are major hallmarks of MM, which implicates an aberrant DNA repair mechanism. Studies have implicated a role for CDK12 in the control of expression of DNA damage response genes. In this study, we examined the effect of a small molecule inhibitor of CDK12\u2013THZ531 on MM cells. Treatment of MM cells with THZ531 led to heightened cell death accompanied by an extensive effect on gene expression changes. In particular, we observed downregulation of genes involved in DNA repair pathways. With this insight, we extended our study to identify synthetic lethal mechanisms that could be exploited for the treatment of MM cells. Combination of THZ531 with either DNA-PK inhibitor (KU-0060648) or PARP inhibitor (Olaparib) led to synergistic cell death. In addition, combination treatment of THZ531 with Olaparib significantly reduced tumor burden in animal models. Our findings suggest that using a CDK12 inhibitor in combination with other DNA repair inhibitors may establish an effective therapeutic regimen to benefit myeloma patients.<\/jats:p>","DOI":"10.3390\/ijms23031207","type":"journal-article","created":{"date-parts":[[2022,1,23]],"date-time":"2022-01-23T20:32:52Z","timestamp":1642969972000},"page":"1207","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["THZ531 Induces a State of BRCAness in Multiple Myeloma Cells: Synthetic Lethality with Combination Treatment of THZ 531 with DNA Repair Inhibitors"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1792-312X","authenticated-orcid":false,"given":"Pavithra","family":"Shyamsunder","sequence":"first","affiliation":[{"name":"Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore"},{"name":"Cancer & Stem Cell Biology Programme, Duke-NUS Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shree Pooja","family":"Sridharan","sequence":"additional","affiliation":[{"name":"Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Madan","sequence":"additional","affiliation":[{"name":"Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pushkar","family":"Dakle","sequence":"additional","affiliation":[{"name":"Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cao","family":"Zeya","sequence":"additional","affiliation":[{"name":"Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepika","family":"Kanojia","sequence":"additional","affiliation":[{"name":"Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2578-8335","authenticated-orcid":false,"given":"Wee-Joo","family":"Chng","sequence":"additional","affiliation":[{"name":"Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore"},{"name":"Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Hospital, Singapore 119074, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Tiong","family":"Ong","sequence":"additional","affiliation":[{"name":"Cancer & Stem Cell Biology Programme, Duke-NUS Medical School, Singapore 169857, Singapore"},{"name":"Department of Haematology, Singapore General Hospital, Singapore 169608, Singapore"},{"name":"Department of Medical Oncology, National Cancer Centre, Singapore 169610, Singapore"},{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Phillip","family":"Koeffler","sequence":"additional","affiliation":[{"name":"Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore"},{"name":"Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Hospital, Singapore 119074, Singapore"},{"name":"Cedars-Sinai Medical Center, Division of Hematology\/Oncology, UCLA School of Medicine, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Saitoh, T., and Oda, T. (2021). DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment. Cancers, 13.","DOI":"10.3390\/cancers13030504"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Herrero, A.B., San Miguel, J., and Gutierrez, N.C. (2015). Deregulation of DNA double-strand break repair in multiple myeloma: Implications for genome stability. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121581"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2290","DOI":"10.1182\/blood-2007-05-089193","article-title":"Dysfunctional homologous recombination mediates genomic instability and progression in myeloma","volume":"113","author":"Shammas","year":"2009","journal-title":"Blood"},{"key":"ref_4","first-page":"66","article-title":"Impaired NHEJ function in multiple myeloma","volume":"660","author":"Yang","year":"2009","journal-title":"Mutat. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1093\/carcin\/bgh187","article-title":"DNA mismatch repair pathway defects in the pathogenesis and evolution of myeloma","volume":"25","author":"Velangi","year":"2004","journal-title":"Carcinogenesis"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1158\/2159-8290.CD-20-1503","article-title":"Synthetic Lethality in Cancer Therapeutics: The Next Generation","volume":"11","author":"Setton","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1056\/NEJMe0903044","article-title":"Synthetic lethality\u2014A new direction in cancer-drug development","volume":"361","author":"Iglehart","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1038\/nrc1691","article-title":"The concept of synthetic lethality in the context of anticancer therapy","volume":"5","author":"Kaelin","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/nrc2342","article-title":"DNA repair pathways as targets for cancer therapy","volume":"8","author":"Helleday","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.molcel.2015.10.040","article-title":"Targeting the DNA Damage Response in Cancer","volume":"60","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1038\/nature03443","article-title":"Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase","volume":"434","author":"Bryant","year":"2005","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nature03445","article-title":"Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy","volume":"434","author":"Farmer","year":"2005","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1056\/NEJM199911183412102","article-title":"Antitumor activity of thalidomide in refractory multiple myeloma","volume":"341","author":"Singhal","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1056\/NEJMoa030288","article-title":"A phase 2 study of bortezomib in relapsed, refractory myeloma","volume":"348","author":"Richardson","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1182\/blood-2005-01-0034","article-title":"Cyclin D dysregulation: An early and unifying pathogenic event in multiple myeloma","volume":"106","author":"Bergsagel","year":"2005","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"451","DOI":"10.4161\/cbt.19589","article-title":"Cyclin dependent kinases in cancer: Potential for therapeutic intervention","volume":"13","author":"Canavese","year":"2012","journal-title":"Cancer Biol. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1182\/blood-2014-05-573741","article-title":"Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma","volume":"125","author":"Kumar","year":"2015","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4843","DOI":"10.1128\/MCB.19.7.4843","article-title":"BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site","volume":"19","author":"Ruffner","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.molcel.2009.06.036","article-title":"Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage","volume":"35","author":"Johnson","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1038\/emboj.2008.61","article-title":"A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor","volume":"27","author":"Turner","year":"2008","journal-title":"EMBO J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3847","DOI":"10.1182\/blood-2010-08-304022","article-title":"RNAi screen of the druggable genome identifies modulators of proteasome inhibitor sensitivity in myeloma including CDK5","volume":"117","author":"Zhu","year":"2011","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1158\/0008-5472.CAN-11-2196","article-title":"Transcriptional and nontranscriptional functions of E2F1 in response to DNA damage","volume":"72","author":"Biswas","year":"2012","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1158\/1535-7163.MCT-08-0659","article-title":"Pharmacogenomic approach for the identification of novel determinants of acquired resistance to oxaliplatin in colorectal cancer","volume":"8","author":"Bandres","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/j.1601-0825.2011.01791.x","article-title":"A systematic review of medical interventions for oral submucous fibrosis and future research opportunities","volume":"17","author":"Kerr","year":"2011","journal-title":"Oral Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2980","DOI":"10.1021\/jm200064p","article-title":"Pyrazolo[4,3-d]pyrimidine bioisostere of roscovitine: Evaluation of a novel selective inhibitor of cyclin-dependent kinases with antiproliferative activity","volume":"54","author":"Jorda","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e507","DOI":"10.1016\/j.ijrobp.2012.05.035","article-title":"AZD5438, an inhibitor of Cdk1, 2, and 9, enhances the radiosensitivity of non-small cell lung carcinoma cells","volume":"84","author":"Raghavan","year":"2012","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1158\/1535-7163.MCT-15-0660","article-title":"A Cyclin-Dependent Kinase Inhibitor, Dinaciclib, Impairs Homologous Recombination and Sensitizes Multiple Myeloma Cells to PARP Inhibition","volume":"15","author":"Alagpulinsa","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.ccell.2017.12.009","article-title":"EWS\/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma","volume":"33","author":"Iniguez","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/nrm2008","article-title":"Mechanism of homologous recombination: Mediators and helicases take on regulatory functions","volume":"7","author":"Sung","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1007\/PL00000944","article-title":"Potent induction of wild-type p53-dependent transcription in tumour cells by a synthetic inhibitor of cyclin-dependent kinases","volume":"58","author":"Kotala","year":"2001","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1158\/0008-5472.CAN-07-2395","article-title":"The cyclin-dependent kinase inhibitor flavopiridol potentiates the effects of topoisomerase I poisons by suppressing Rad51 expression in a p53-dependent manner","volume":"68","author":"Ambrosini","year":"2008","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3389\/fphar.2013.00005","article-title":"Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond","volume":"4","author":"Davidson","year":"2013","journal-title":"Front. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"98","DOI":"10.3389\/fonc.2017.00098","article-title":"Targeting Ongoing DNA Damage in Multiple Myeloma: Effects of DNA Damage Response Inhibitors on Plasma Cell Survival","volume":"7","author":"Herrero","year":"2017","journal-title":"Front. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6368","DOI":"10.1182\/blood-2011-06-363911","article-title":"Bortezomib-induced \u201cBRCAness\u201d sensitizes multiple myeloma cells to PARP inhibitors","volume":"118","author":"Neri","year":"2011","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1101\/gad.16962311","article-title":"The Cyclin K\/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes","volume":"25","author":"Blazek","year":"2011","journal-title":"Genes Dev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1038\/cdd.2015.157","article-title":"Cdk12 is essential for embryonic development and the maintenance of genomic stability","volume":"23","author":"Juan","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1158\/0008-5472.CAN-13-2541","article-title":"Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1\/2 inhibitor sensitivity","volume":"74","author":"Bajrami","year":"2014","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9247","DOI":"10.1074\/jbc.M114.551143","article-title":"Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors","volume":"289","author":"Joshi","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/s41422-018-0023-9","article-title":"SUMO suppresses and MYC amplifies transcription globally by regulating CDK9 sumoylation","volume":"28","author":"Yu","year":"2018","journal-title":"Cell Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ctrv.2016.09.003","article-title":"Role and therapeutic potential of CDK12 in human cancers","volume":"50","author":"Chila","year":"2016","journal-title":"Cancer Treat. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8109","DOI":"10.1158\/0008-5472.CAN-06-0140","article-title":"Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition","volume":"66","author":"McCabe","year":"2006","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/cr.2007.111","article-title":"Regulation of DNA double-strand break repair pathway choice","volume":"18","author":"Shrivastav","year":"2008","journal-title":"Cell Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"635","DOI":"10.3389\/fonc.2019.00635","article-title":"DNA-PK as an Emerging Therapeutic Target in Cancer","volume":"9","author":"Mohiuddin","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.pbiomolbio.2014.12.003","article-title":"The DNA-dependent protein kinase: A multifunctional protein kinase with roles in DNA double strand break repair and mitosis","volume":"117","author":"Jette","year":"2015","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6182","DOI":"10.1128\/MCB.00355-08","article-title":"The catalytic subunit of DNA-dependent protein kinase regulates proliferation, telomere length, and genomic stability in human somatic cells","volume":"28","author":"Ruis","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1038\/nm.2377","article-title":"Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition","volume":"17","author":"Johnson","year":"2011","journal-title":"Nat. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1016\/j.celrep.2016.10.077","article-title":"CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer","volume":"17","author":"Johnson","year":"2016","journal-title":"Cell Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1136\/gutjnl-2019-318506","article-title":"CDK12 inhibition mediates DNA damage and is synergistic with sorafenib treatment in hepatocellular carcinoma","volume":"69","author":"Wang","year":"2020","journal-title":"Gut"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/nbt.3519","article-title":"Near-optimal probabilistic RNA-seq quantification","volume":"34","author":"Bray","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.12688\/f1000research.7563.1","article-title":"Differential analyses for RNA-seq: Transcript-level estimates improve gene-level inferences","volume":"4","author":"Soneson","year":"2015","journal-title":"F1000Research"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"}],"updated-by":[{"DOI":"10.3390\/ijms27125312","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T00:00:00Z","timestamp":1642723200000}}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1207\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T01:52:56Z","timestamp":1781229176000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1207"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,21]]},"references-count":51,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23031207"],"URL":"https:\/\/doi.org\/10.3390\/ijms23031207","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,21]]}}}