Pan-Raf co-operates with PI3K-dependent signalling and critically contributes to myeloma cell survival independently...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Direct targeting of oncogenic RAS is challenging due to a lack of effective inhibitors.
• RAS effector pathways, such as the Raf complex, represent potential alternative therapeutic targets in cancer.
• Multiple myeloma (MM) is a hematologic malignancy with complex signaling pathway involvement.

Purpose of the Study:

• To investigate the role of the Raf complex in multiple myeloma (MM) pathobiology.
• To evaluate the efficacy of pan-Raf inhibition as a therapeutic strategy for MM.
• To explore combination therapy with PI3K inhibition for enhanced anti-MM effects.

Main Methods:

• Analysis of Raf isoform and downstream MEK/ERK activation in MM cells.
• Inhibition of Raf isoforms using RNA interference (RNAi) and pharmacological inhibitors.
• Assessment of apoptosis induction in human MM cell lines, primary MM cells, and a syngeneic MM mouse model.
• Transcriptome analysis to identify affected signaling pathways.
• Combination therapy studies with PI3K inhibitors in vitro and in vivo.

Main Results:

• Frequent overexpression and activation of the Raf complex (A-, B-, and C-Raf) and MEK1,2/ERK1,2 were observed in MM cells.
• Concomitant pan-Raf inhibition strongly induced apoptosis in MM cells, irrespective of RAS mutation status.
• Pan-Raf inhibition affected PI3K-dependent signaling, indicating crosstalk between RAS/Raf and PI3K/mTOR/Akt pathways.
• Combined pan-Raf and PI3K inhibition demonstrated enhanced anti-MM efficacy in vitro and in vivo.
• This combination therapy was effective in models resistant to carfilzomib and lenalidomide.

Conclusions:

• The Raf complex is a critical mediator in MM pathobiology.
• Pan-Raf inhibition is a potent anti-MM strategy, involving both MEK-dependent and -independent mechanisms.
• Combining pan-Raf inhibition with PI3K inhibition offers a promising therapeutic approach for MM, including drug-resistant cases, suitable for clinical translation.