The Rationale for the Dual-Targeting Therapy for RSK2 and AKT in Multiple Myeloma

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Multiple myeloma (MM) exhibits significant patient and intraclonal heterogeneity.
• PDPK1 kinase is universally active in MM, driving proliferation and survival irrespective of genetic profiles.
• PDPK1 regulates key signaling pathways, including RSK2 and AKT.

Purpose of the Study:

• To investigate the therapeutic efficacy of simultaneously inhibiting two major PDPK1 substrates, RSK2 and AKT, in MM.
• To elucidate the mechanism of action for this dual-targeting strategy.
• To evaluate the impact on myeloma cell proliferation, survival, and associated molecular pathways.

Main Methods:

• Utilized BI-D1870 (RSK2 inhibitor) and ipatasertib (AKT inhibitor) in combination.
• Tested the dual blockade on human MM-derived cell lines (HMCLs).
• Assessed anti-tumor effects, apoptosis induction (BIM, BID activation), and molecular pathway modulation.

Main Results:

• Combined BI-D1870 and ipatasertib demonstrated additive to synergistic anti-tumor effects in HMCLs.
• The dual blockade enhanced apoptosis through BIM and BID activation.
• Significant molecular effects were observed on gene sets related to MYC, mTOR, STK33, ribosomal biogenesis, and cell-extrinsic factors.

Conclusions:

• Dual blockade of RSK2 and AKT provides a rational therapeutic strategy for MM.
• This approach may overcome challenges posed by MM's cytogenetic and molecular heterogeneity.
• Further investigation into this dual-targeting strategy is warranted for MM treatment.