MDM2 Drives Proteasome Inhibitor Resistance and Represents a TP53-Independent Therapeutic Vulnerability in Multiple Myeloma

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–stromal 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.

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Journal
Cells
Published
2026-05-01
DOI
https://doi.org/10.3390/cells15090831
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
0.00

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article

MDM2 Drives Proteasome Inhibitor Resistance and Represents a TP53-Independent Therapeutic Vulnerability in Multiple Myeloma

Mattia D’Agostino, M. Porro, Veronica Manicardi, Alessia Ciarrocchi et al.
Cells
Ubiquitin and proteasome pathways
article

MDM2 Drives Proteasome Inhibitor Resistance and Represents a TP53-Independent Therapeutic Vulnerability in Multiple Myeloma

Mattia D’Agostino, M. Porro, Veronica Manicardi, Alessia Ciarrocchi, Tina Paradžik, Eugenio Morelli, Domenica Ronchetti, Benedetta Donati, Alessandra Larocca, Cecilia Bandini, Benedetto Bruno, Antonino Neri, Michela Cumerlato, Maria Labrador, Elisabetta Mereu, Andrew Chatr‐aryamontri, Roberto Piva, Sara Cozzubbo, Francesca Gay
article en

Abstract

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–stromal 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.

CellsVol. 15(9)
United Nations Industrial Development Organization (AT), University of Milan (IT), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Azienda Sanitaria Unità Locale di Reggio Emilia (IT), Institute for Research in Immunology and Cancer (CA), Ruđer Bošković Institute (HR), Candiolo Cancer Institute (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University of Turin (IT)
Associazione Italiana per la Ricerca sul Cancro
Good health and well-being
Openalex Percentile: Top 10%
Ubiquitin and proteasome pathways
DOIOpen Access PDFOpenAlex
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