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Increased resistance to proteasome inhibitors in multiple myeloma mediated by cIAP2--implications for a combinatorial

Charlotte Fristedt Duvefelt1, Susanne Lub2, Prasoon Agarwal1

  • 1Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Oncotarget
|June 4, 2015
PubMed

Insights

Cellular inhibitor of apoptosis 2 (cIAP2) overexpression in multiple myeloma (MM) with TRAF3 mutations causes drug resistance. Targeting cIAP2 with inhibitors like AT-406 can overcome this resistance, improving treatment efficacy.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Multiple myeloma (MM) treatment is challenged by drug resistance, leading to relapse in most patients.
  • Identifying novel resistance mechanisms is crucial for developing effective combinatorial therapies.
  • Aberrant NF-κB signaling and heterogeneous cIAP2 expression are noted in MM.

Purpose of the Study:

  • To investigate the role of cellular inhibitor of apoptosis 2 (cIAP2) in mediating drug resistance in MM.
  • To elucidate mechanisms of cIAP2-induced resistance in MM cells with TRAF3 deletion/mutation.
  • To explore strategies for overcoming cIAP2-mediated resistance through combinatorial treatment.

Main Methods:

  • Utilized TRAF3 deleted/mutated MM cell lines.
  • Assessed drug sensitivity to proteasome inhibitors (bortezomib, MG132, carfilzomib) in cIAP2 overexpressing cells.
  • Performed gene expression analysis to identify differentially expressed genes.
  • Evaluated the efficacy of combining IAP inhibitor AT-406 with bortezomib.

Main Results:

  • cIAP2 overexpression correlated with decreased sensitivity to bortezomib, MG132, and carfilzomib in MM cells.
  • cIAP2 overexpression led to differential expression of 440 genes.
  • The IAP inhibitor AT-406 enhanced the anti-MM effect of bortezomib in TRAF3-mutated/deleted cell lines.

Conclusions:

  • cIAP2 is a key mediator of bortezomib resistance in multiple myeloma cells with TRAF3 deletion/mutation.
  • cIAP2 represents a potential therapeutic target for overcoming drug resistance in a subset of MM patients.
  • Combinatorial treatment targeting cIAP2 alongside proteasome inhibitors offers a promising strategy for MM.
Keywords:
antagonist of inhibitors of apoptosis proteinscellular inhibitor of apoptosis protein 2drug resistancemultiple myelomaproteasome inhibitors

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