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Apoptosis reprogramming triggered by splicing inhibitors sensitizes multiple myeloma cells to Venetoclax treatment

Debora Soncini1, Claudia Martinuzzi2, Pamela Becherini2

  • 1Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Italy.

Haematologica
|October 21, 2021
PubMed

Insights

Targeting aberrant splicing in multiple myeloma (MM) offers a new therapeutic strategy. Modulating splicing impairs cancer cell growth and primes them for BCL2 inhibitors, improving treatment outcomes for all MM patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Therapeutic resistance is a major challenge in cancer treatment.
  • Aberrant splicing is prevalent in cancer cells and represents a potential therapeutic target.
  • Multiple myeloma (MM) cells exhibit deregulation of spliceosome machinery components.

Purpose of the Study:

  • To investigate the expression of spliceosome machinery components in MM cells.
  • To evaluate the impact of splicing modulation on MM cell growth and viability.
  • To explore the role of splicing in priming MM cells for BCL2 inhibitor therapy.

Main Methods:

  • Comprehensive gene expression analysis of spliceosome components in MM cells.
  • Pharmacological and genetic modulation of splicing.
  • Transcriptomic analysis of BCL2 family members.
  • In vitro and in vivo studies using MM cell lines and patient-derived cells.

Main Results:

  • Confirmed deregulation of spliceosome machinery in MM cells compared to normal plasma cells.
  • Pharmacological and genetic modulation of splicing impaired MM cell growth and survival.
  • Demonstrated that splicing deregulation affects BCL2 family members, including decreased MCL1 expression.
  • Showed that splicing modulation primes MM cells for Venetoclax activity, irrespective of t(11;14) status.

Conclusions:

  • Splicing modulation is a viable strategy to target vulnerabilities in multiple myeloma.
  • Reprogramming apoptotic dependencies through splicing modulation enhances MM cell susceptibility to BCL2 inhibitors.
  • This approach offers a rationale for treating all MM patients with splicing modulators and BCL2 inhibitors.

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