Targeting the RBM39-MEK5 axis synergizes with bortezomib to inhibit the malignant growth of multiple myeloma

Area of Science:

• Molecular Biology
• Oncology
• Cancer Therapeutics

Background:

• Aberrant alternative splicing is a cancer hallmark, often linked to splicing factor overexpression.
• Splicing factor RBM39 is upregulated in multiple myeloma (MM), correlating with poor prognosis.

Purpose of the Study:

• To investigate the role of RBM39 in MM cell survival and proliferation.
• To evaluate indisulam, a RBM39-targeting agent, as a potential MM therapy.
• To explore the therapeutic potential of targeting RBM39 and MEK5 pathways in MM.

Main Methods:

• RBM39 knockdown experiments to assess its impact on MM cell growth.
• In vitro and in vivo studies using indisulam to evaluate its anti-MM effects.
• Analysis of MEK5 splicing alterations and their functional consequences.
• Combination therapy studies with bortezomib targeting RBM39/MEK5 and p65 inhibition.

Main Results:

• RBM39 is essential for MM cell survival and proliferation; its knockdown inhibits tumor growth.
• Indisulam effectively suppresses MM growth in vitro and in vivo by inducing RBM39 degradation.
• RBM39 deletion causes widespread splicing alterations, including MEK5 mis-splicing, inhibiting MM growth.
• Targeting RBM39 or MEK5 synergistically enhances bortezomib cytotoxicity via p65 inhibition.

Conclusions:

• RBM39 is a critical driver of multiple myeloma.
• Indisulam demonstrates therapeutic potential for MM by targeting RBM39.
• Targeting the RBM39-MEK5 axis offers a promising strategy for MM treatment.