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

María Labrador1,2, Sara Cozzubbo1,2, Mariangela Porro1,2

  • 1Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.

Cells
|May 13, 2026
PubMed

Insights

Resistance to proteasome inhibitors (PIs) in multiple myeloma is a challenge. Targeting MDM2 with NVP-CGM097 synergizes with carfilzomib, offering a new therapeutic strategy for PI-resistant multiple myeloma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Proteasome inhibitors (PIs) are crucial for multiple myeloma (MM) treatment.
  • Therapeutic resistance to PIs, especially carfilzomib (CFZ), is a significant clinical hurdle in relapsed/refractory MM.
  • Identifying mechanisms of resistance is vital for developing novel therapeutic strategies.

Purpose of the Study:

  • To identify functional mediators of carfilzomib resistance in multiple myeloma.
  • To investigate the role of MDM2 in proteasome inhibitor response and resistance.
  • To evaluate the therapeutic potential of combining MDM2 inhibition with proteasome inhibitors in MM.

Main Methods:

  • Utilized gain-of-function CRISPR activation and pharmacological screening to identify resistance mediators.
  • Investigated the effects of MDM2 inhibition using NVP-CGM097 in combination with CFZ.
  • Assessed molecular mechanisms including p21 and c-MYC expression, cell-cycle arrest, and DNA damage response.
  • Validated findings in MM-stromal co-cultures and primary patient samples, including TP53-deficient cases.

Main Results:

  • MDM2 was identified as a key modulator of PI response, with its transactivation enhancing MM cell survival and recovery after CFZ exposure.
  • Pharmacologic inhibition of MDM2 with NVP-CGM097 demonstrated synergistic effects with CFZ in both PI-sensitive and PI-resistant MM cell lines, regardless of TP53 status.
  • MDM2 inhibition led to p21 upregulation, cell-cycle arrest, reduced c-MYC, and impaired DNA damage response activation.
  • Genetic silencing of MDM2 mimicked these effects and increased sensitivity to CFZ.
  • The combination therapy showed efficacy in co-culture models and primary patient samples, including those with del(17p), while sparing normal cells.

Conclusions:

  • MDM2 is a functional driver of proteasome inhibitor resistance in multiple myeloma.
  • Combined MDM2 and proteasome inhibition represents a rational and potentially effective therapeutic strategy for MM, including TP53-deficient settings.
  • Targeting MDM2 offers a promising approach to overcome resistance and improve outcomes in multiple myeloma patients.
Keywords:
MDM2TP53drug resistancemultiple myelomaproteasome inhibitorssynthetic lethality

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