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Ceritinib overcomes proteasome inhibitor resistance in multiple myeloma by suppressing the protein folding response

Andrej Besse1, Marianne Kraus2, Tiberiu Totu3

  • 1Laboratory of Experimental Oncology, Division Oncology and Hematology, HOCH Health Ostschweiz, Cantonal Hospital St. Gallen, St. Gallen, Switzerland; Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.

Haematologica
|December 11, 2025
PubMed

Insights

Ceritinib overcomes proteasome inhibitor resistance in multiple myeloma by blocking IGF-1R/INSR signaling. This combination therapy with carfilzomib enhances cell death and warrants clinical investigation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Proteasome inhibitor (PI) resistance is a significant challenge in multiple myeloma (MM) treatment.
  • MM cells rely heavily on insulin and IGF-1 signaling pathways (IGF-1R/INSR) for survival.
  • Understanding resistance mechanisms is crucial for developing effective MM therapies.

Purpose of the Study:

  • To identify novel therapeutic strategies to overcome PI resistance in MM.
  • To investigate the potential of ceritinib, an ALK inhibitor, in combination with carfilzomib for MM treatment.
  • To elucidate the molecular mechanisms by which ceritinib affects MM cell survival under PI treatment.

Main Methods:

  • In vitro and in vivo MM models were utilized.
  • Primary patient-derived MM cells were tested.
  • Ceritinib's effect on IGF-1R/INSR signaling and downstream pathways (PI3K/AKT/mTORC1) was assessed.
  • Synergistic effects of ceritinib and carfilzomib were evaluated.

Main Results:

  • Ceritinib inhibits IGF-1R/INSR activity and downstream signaling in MM cells.
  • Ceritinib combined with carfilzomib demonstrated synergistic efficacy in overcoming PI resistance across models.
  • Ceritinib abrogated the adaptive stress response by inhibiting heat shock proteins (HSP70, BiP) crucial for proteostasis.
  • This led to increased protein aggregation, ER stress, and apoptosis in MM cells.

Conclusions:

  • Ceritinib repurposing with carfilzomib is a safe and translationally relevant strategy to overcome PI resistance in MM.
  • The combination therapy targets the IGF-1R/INSR-mediated adaptive stress response in MM cells.
  • Further clinical investigation in relapsed/refractory MM is warranted.

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