{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:05Z","timestamp":1787027825372,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro (AIRC), Milano, Italy","doi-asserted-by":"publisher","award":["Investigator Grant-21585"],"award-info":[{"award-number":["Investigator Grant-21585"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"award":["Investigator Grant-21585"],"award-info":[{"award-number":["Investigator Grant-21585"]}],"id":[{"id":"https:\/\/ror.org\/02g2x7380","id-type":"ROR","asserted-by":"publisher"}]},{"name":"University of Torino","award":["RILO 2022\u20132025"],"award-info":[{"award-number":["RILO 2022\u20132025"]}]},{"award":["RILO 2022\u20132025"],"award-info":[{"award-number":["RILO 2022\u20132025"]}],"id":[{"id":"https:\/\/ror.org\/048tbm396","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Proteasome inhibitors (PIs) are central to multiple myeloma (MM) therapy; however, resistance remains a major clinical challenge, particularly in relapsed\/refractory disease. To identify functional mediators of carfilzomib (CFZ) resistance, we performed complementary gain-of-function CRISPR activation and pharmacological screening approaches. These unbiased strategies converged on the E3 ubiquitin ligase MDM2 as a modulator of PI response. MDM2 transactivation enhanced MM cell survival and accelerated recovery following CFZ exposure, supporting a causal role in proteotoxic stress tolerance. Pharmacologic inhibition of MDM2 with NVP-CGM097 synergized with CFZ across multiple PI-sensitive and PI-resistant MM cell lines, irrespective of TP53 status. Mechanistically, MDM2 inhibition induced p21 upregulation, cell-cycle arrest, and reduced c-MYC expression, accompanied by impaired activation of DNA damage response mediators. Genetic silencing of MDM2 phenocopied these effects and increased CFZ sensitivity. Importantly, the combination retained efficacy in MM\u2013stromal co-culture models and in primary patient samples, including cases harboring del(17p), while sparing normal peripheral blood mononuclear cells. Collectively, these findings identify MDM2 as a functional driver of PI resistance and support combined MDM2 and proteasome inhibition as a rational therapeutic strategy in MM, including TP53-deficient contexts.<\/jats:p>","DOI":"10.3390\/cells15090831","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T16:54:07Z","timestamp":1777654447000},"page":"831","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["MDM2 Drives Proteasome Inhibitor Resistance and Represents a TP53-Independent Therapeutic Vulnerability in Multiple Myeloma"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8934-7235","authenticated-orcid":false,"given":"Mar\u00eda","family":"Labrador","sequence":"first","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Molecular Biotechnology Center (MBC) \u201cGuido Tarone\u201d, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Cozzubbo","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Molecular Biotechnology Center (MBC) \u201cGuido Tarone\u201d, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5131-4750","authenticated-orcid":false,"given":"Mariangela","family":"Porro","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Molecular Biotechnology Center (MBC) \u201cGuido Tarone\u201d, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Cumerlato","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Molecular Biotechnology Center (MBC) \u201cGuido Tarone\u201d, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Bandini","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Molecular Biotechnology Center (MBC) \u201cGuido Tarone\u201d, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Mereu","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Molecular Biotechnology Center (MBC) \u201cGuido Tarone\u201d, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2306-8932","authenticated-orcid":false,"given":"Tina","family":"Paradzik","sequence":"additional","affiliation":[{"name":"Division of Physical Chemistry, Rudjer Boskovic Institute, 10000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9163-8194","authenticated-orcid":false,"given":"Benedetta","family":"Donati","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2490-7283","authenticated-orcid":false,"given":"Veronica","family":"Manicardi","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4824-3445","authenticated-orcid":false,"given":"Domenica","family":"Ronchetti","sequence":"additional","affiliation":[{"name":"Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1711-6996","authenticated-orcid":false,"given":"Mattia","family":"D\u2019Agostino","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Division of Hematology, AOU Citt\u00e0 della Salute e della Scienza di Torino, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Larocca","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Division of Hematology, AOU Citt\u00e0 della Salute e della Scienza di Torino, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8619-412X","authenticated-orcid":false,"given":"Francesca","family":"Gay","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Division of Hematology, AOU Citt\u00e0 della Salute e della Scienza di Torino, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7299-6770","authenticated-orcid":false,"given":"Benedetto","family":"Bruno","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Division of Hematology, AOU Citt\u00e0 della Salute e della Scienza di Torino, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5541-2075","authenticated-orcid":false,"given":"Alessia","family":"Ciarrocchi","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1589-9982","authenticated-orcid":false,"given":"Andrew","family":"Chatr-Aryamontri","sequence":"additional","affiliation":[{"name":"ChemoGenix CRISPR Screening Platform, Institute for Research in Immunology and Cancer, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonino","family":"Neri","sequence":"additional","affiliation":[{"name":"Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8850-0442","authenticated-orcid":false,"given":"Eugenio","family":"Morelli","sequence":"additional","affiliation":[{"name":"Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Italy"},{"name":"Department of Oncology, University of Turin, 10124 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2273-3470","authenticated-orcid":false,"given":"Roberto","family":"Piva","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Molecular Biotechnology Center (MBC) \u201cGuido Tarone\u201d, 10126 Turin, Italy"},{"name":"Division of Hematology, AOU Citt\u00e0 della Salute e della Scienza di Torino, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41572-024-00529-7","article-title":"Multiple myeloma","volume":"10","author":"Malard","year":"2024","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"132","DOI":"10.6004\/jnccn.2025.0023","article-title":"NCCN Guidelines\u00ae Insights: Multiple Myeloma, Version 1.2025: Featured Updates to the NCCN Guidelines\u00ae","volume":"23","author":"Kumar","year":"2025","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nrclinonc.2016.206","article-title":"Proteasome inhibitors in cancer therapy","volume":"14","author":"Manasanch","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1146\/annurev-pharmtox-010919-023603","article-title":"Proteasome Inhibitor Drugs","volume":"60","author":"Fricker","year":"2020","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.hoc.2023.12.016","article-title":"Proteasome Inhibitors in Multiple Myeloma: Biological Insights on Mechanisms of Action or Resistance Informed by Functional Genomics","volume":"38","author":"Mitsiades","year":"2024","journal-title":"Hematol. Oncol. Clin. N. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3040","DOI":"10.1182\/blood-2008-08-172734","article-title":"The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition","volume":"113","author":"Bianchi","year":"2009","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.tips.2023.05.006","article-title":"Overcoming proteasome inhibitor resistance in the immunotherapy era","volume":"44","author":"Talbot","year":"2023","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Paradzik, T., Bandini, C., Mereu, E., Labrador, M., Taiana, E., Amodio, N., Neri, A., and Piva, R. (2021). The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma. Cancers, 13.","DOI":"10.3390\/cancers13061235"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/s41591-021-01232-w","article-title":"Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing","volume":"27","author":"Cohen","year":"2021","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.3324\/haematol.2021.279360","article-title":"Comprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities","volume":"107","author":"Giesen","year":"2022","journal-title":"Haematologica"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s11523-024-01122-4","article-title":"Multiple Myeloma: Improved Outcomes Resulting from a Rapidly Expanding Number of Therapeutic Options","volume":"20","author":"Mettias","year":"2025","journal-title":"Target. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/BF03402141","article-title":"Mdm2: The ups and downs","volume":"5","author":"Oren","year":"1999","journal-title":"Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1158\/1078-0432.CCR-12-0053","article-title":"Molecular pathways: Targeting Mdm2 and Mdm4 in cancer therapy","volume":"19","author":"Li","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1101\/gad.347872.120","article-title":"The roles and regulation of MDM2 and MDMX: It is not just about p53","volume":"35","author":"Klein","year":"2021","journal-title":"Genes Dev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1182\/blood.V90.5.1982","article-title":"MDM2 protein overexpression promotes proliferation and survival of multiple myeloma cells","volume":"90","author":"Teoh","year":"1997","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1007\/s10142-022-00880-6","article-title":"Discovery of the oncogenic MDM2, a direct binding target of berberine and a potential therapeutic, in multiple myeloma","volume":"22","author":"Li","year":"2022","journal-title":"Funct. Integr. Genom."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"567","DOI":"10.4161\/cbt.10.6.12535","article-title":"Molecular mechanisms of nutlin-induced apoptosis in multiple myeloma: Evidence for p53-transcription-dependent and -independent pathways","volume":"10","author":"Saha","year":"2010","journal-title":"Cancer Biol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41375-018-0196-8","article-title":"A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis","volume":"33","author":"Walker","year":"2019","journal-title":"Leukemia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1182\/blood-2018-05-850826","article-title":"IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies","volume":"133","author":"Bergaggio","year":"2019","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s40164-023-00434-x","article-title":"Lysin (K)-specific demethylase 1 inhibition enhances proteasome inhibitor response and overcomes drug resistance in multiple myeloma","volume":"12","author":"Bandini","year":"2023","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e415","DOI":"10.3324\/haematol.2018.207704","article-title":"A metabolic switch in proteasome inhibitor-resistant multiple myeloma ensures higher mitochondrial metabolism, protein folding and sphingomyelin synthesis","volume":"104","author":"Besse","year":"2019","journal-title":"Haematologica"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2198","DOI":"10.1038\/leu.2016.102","article-title":"Proteasome inhibitor-adapted myeloma cells are largely independent from proteasome activity and show complex proteomic changes, in particular in redox and energy metabolism","volume":"30","author":"Soriano","year":"2016","journal-title":"Leukemia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nprot.2017.016","article-title":"Genome-scale CRISPR-Cas9 knockout and transcriptional activation screening","volume":"12","author":"Joung","year":"2017","journal-title":"Nat. Protoc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6801","DOI":"10.1038\/s41388-019-0924-1","article-title":"The Hippo pathway modulates resistance to BET proteins inhibitors in lung cancer cells","volume":"38","author":"Gobbi","year":"2019","journal-title":"Oncogene"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Mereu, E., Abbo, D., Paradzik, T., Cumerlato, M., Bandini, C., Labrador, M., Maccagno, M., Ronchetti, D., Manicardi, V., and Neri, A. (2023). Euchromatic Histone Lysine Methyltransferase 2 Inhibition Enhances Carfilzomib Sensitivity and Overcomes Drug Resistance in Multiple Myeloma Cell Lines. Cancers, 15.","DOI":"10.3390\/cancers15082199"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wang, S., Oliveira-Silveira, J., Fang, G., and Kang, J. (2024). High-content analysis identified synergistic drug interactions between INK128, an mTOR inhibitor, and HDAC inhibitors in a non-small cell lung cancer cell line. BMC Cancer, 24.","DOI":"10.1186\/s12885-024-12057-4"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Cumerlato, M., Maccagno, M., Labrador, M., Luciano, B., Mereu, E., Porro, M., Bandini, C., Furlan, M., Maisano, D., and D\u2019Agostino, M. (2026). Bedaquiline Amplifies Proteasome Inhibitor Efficacy and Overcomes Resistance in Multiple Myeloma. Haematologica, Online ahead of printing.","DOI":"10.3324\/haematol.2025.300157"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Faruq, O., Zhao, D., Shrestha, M., Vecchione, A., Zacksenhaus, E., and Chang, H. (2022). Targeting an MDM2\/MYC Axis to Overcome Drug Resistance in Multiple Myeloma. Cancers, 14.","DOI":"10.3390\/cancers14061592"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"16000","DOI":"10.1074\/jbc.M312264200","article-title":"MDM2 is a negative regulator of p21WAF1\/CIP1, independent of p53","volume":"279","author":"Zhang","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1126\/science.274.5289.948","article-title":"Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain","volume":"274","author":"Kussie","year":"1996","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3609","DOI":"10.1182\/blood-2005-04-1489","article-title":"Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma","volume":"106","author":"Chatterjee","year":"2005","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Gu, D., Wang, S., Kuiatse, I., Wang, H., He, J., Dai, Y., Jones, R.J., Bjorklund, C.C., Yang, J., and Grant, S. (2014). Inhibition of the MDM2 E3 Ligase induces apoptosis and autophagy in wild-type and mutant p53 models of multiple myeloma, and acts synergistically with ABT-737. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0103015"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6348","DOI":"10.1021\/acs.jmedchem.5b00810","article-title":"Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors","volume":"58","author":"Holzer","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5311","DOI":"10.1158\/1078-0432.CCR-11-0476","article-title":"In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells","volume":"17","author":"Chauhan","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1158\/0008-5472.CAN-08-3732","article-title":"Mdm2 affects genome stability independent of p53","volume":"69","author":"Bouska","year":"2009","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e2102420118","DOI":"10.1073\/pnas.2102420118","article-title":"MDM2, MDMX, and p73 regulate cell-cycle progression in the absence of wild-type p53","volume":"118","author":"Klein","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1128\/MCB.19.5.3257","article-title":"MDM2 suppresses p73 function without promoting p73 degradation","volume":"19","author":"Zeng","year":"1999","journal-title":"Mol. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/S0960-9822(99)80367-4","article-title":"MDM2 and MDMX bind and stabilize the p53-related protein p73","volume":"9","author":"Ongkeko","year":"1999","journal-title":"Curr. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"18771","DOI":"10.1074\/jbc.M413387200","article-title":"Mdm2 binds to Nbs1 at sites of DNA damage and regulates double strand break repair","volume":"280","author":"Alt","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1158\/1541-7786.MCR-15-0089","article-title":"Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells","volume":"13","author":"Carrillo","year":"2015","journal-title":"Mol. Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1158\/0008-5472.CAN-22-3173","article-title":"Proteasome Inhibition Sensitizes Liposarcoma to MDM2 Inhibition with Nutlin-3 by Activating the ATF4\/CHOP Stress Response Pathway","volume":"83","author":"Ludwig","year":"2023","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1007\/s10637-019-00840-1","article-title":"Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced P53 wild-type solid tumors or multiple myeloma","volume":"38","author":"Gluck","year":"2020","journal-title":"Investig. New Drugs"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1158\/1078-0432.CCR-21-1295","article-title":"Results from a First-in-Human Phase I Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type TP53 Solid Tumors and Acute Leukemia","volume":"28","author":"Stein","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1158\/1535-7163.MCT-15-0429","article-title":"Inhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097","volume":"14","author":"Weisberg","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"19503","DOI":"10.1021\/acs.jmedchem.4c01818","article-title":"Discovery of MD-265: A Potent MDM2 Degrader That Achieves Complete Tumor Regression and Improves Long-Term Survival of Mice with Leukemia","volume":"67","author":"Aguilar","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Goerg, A., Piendl, G., Albert, V., Ortmann, O., Wege, A.K., and Brockhoff, G. (2025). Mdm2 targeting via PROteolysis TArgeting Chimeras (PROTAC) is efficient in p53 wildtype, p53-mutated, and abemaciclib-resistant estrogen receptor-positive cell lines and superior to mdm2 inhibition. BMC Cancer, 25.","DOI":"10.1186\/s12885-025-14361-z"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1158\/2159-8290.CD-22-1131","article-title":"Targeted MDM2 Degradation Reveals a New Vulnerability for p53-Inactivated Triple-Negative Breast Cancer","volume":"13","author":"Adams","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Kandarpa, M., Peterson, L.F., Potu, H., Ramappan, M., Liu, Y., Polk, A., Wang, S., and Talpaz, M. (2026). Activity of PROTAC MDM2 degrader in primary leukemia cells and PDX models. Leukemia, Online ahead of printing.","DOI":"10.1038\/s41375-026-02957-8"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1158\/1535-7163.MCT-23-0783","article-title":"Discovery and Characterization of Brigimadlin, a Novel and Highly Potent MDM2-p53 Antagonist Suitable for Intermittent Dose Schedules","volume":"23","author":"Gollner","year":"2024","journal-title":"Mol. Cancer Ther."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/9\/831\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T16:59:30Z","timestamp":1777654770000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/9\/831"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,1]]},"references-count":49,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cells15090831"],"URL":"https:\/\/doi.org\/10.3390\/cells15090831","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,1]]}}}