PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma...

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• The phosphoinositide-3-kinase/protein kinase B (PI3K-AKT) pathway is frequently upregulated in multiple myeloma (MM).
• Specific roles of PI3K isoforms, particularly PI3K p110δ (PI3Kδ) and PI3K p110γ (PI3Kγ), in MM pathogenesis remain incompletely understood.

Purpose of the Study:

• To investigate the distinct and combined roles of PI3Kδ and PI3Kγ isoforms in regulating multiple myeloma cell proliferation and interactions within the bone marrow microenvironment.
• To evaluate the therapeutic potential of dual PI3Kδ/γ inhibition in preclinical models of MM.

Main Methods:

• Utilized short hairpin RNA (shRNA) lentivirus-mediated knockdown to target PI3Kδ and PI3Kγ expression in MM cells.
• Employed pharmacologic inhibition using isoform-specific inhibitors and the dual PI3Kδ/γ inhibitor duvelisib.
• Assessed MM cell adhesion, migration, apoptosis, and tumor burden in vitro and in vivo xenograft models.

Main Results:

• MM cell adhesion and migration were identified as PI3Kγ-specific functions, unaffected by PI3Kδ inhibition.
• Dual PI3Kδ/γ inhibition with duvelisib decreased AKT phosphorylation and induced apoptosis in MM cells co-cultured with bone marrow stromal cells (BMSC) and interleukin-6.
• Targeting PI3Kδ or PI3Kγ alone via shRNA did not improve survival in NSG mice xenotransplanted with MM cells.
• Duvelisib treatment significantly reduced MM tumor burden in vivo.

Conclusions:

• PI3Kδ and PI3Kγ isoforms exhibit distinct functions in multiple myeloma.
• Combined PI3Kδ/γ isoform inhibition demonstrates significant anti-myeloma activity, supporting its investigation as a therapeutic strategy.
• These findings provide a scientific rationale for clinical trials evaluating dual PI3Kδ/γ inhibition in patients with multiple myeloma.