Dual targeting of PI3K and BCL-2 overcomes ibrutinib resistance in aggressive mantle cell lymphoma

Area of Science:

• Oncology
• Hematology
• Molecular Biology

Background:

• Ibrutinib is effective in mantle cell lymphoma (MCL), but resistance develops in about one-third of patients.
• Acquired resistance to ibrutinib in MCL is nearly universal, often rendering salvage chemotherapy ineffective.
• Mechanisms of ibrutinib resistance involve genetic, epigenetic, and tumor microenvironment factors, leading to signaling network rewiring.

Purpose of the Study:

• To identify signaling network rewiring in ibrutinib-resistant MCL.
• To evaluate the therapeutic potential of dual targeting BCL-2 and PI3-kinase pathways in preclinical models of ibrutinib resistance.

Main Methods:

• Utilized in vitro and in vivo models of primary and secondary ibrutinib resistance.
• Analyzed post-ibrutinib treatment clinical samples.
• Assessed the combination of venetoclax (BCL-2 inhibitor) and duvelisib (PI3Kδ/γ inhibitor) at clinically relevant doses.

Main Results:

• Dual targeting of BCL-2 and PI3-kinase pathways demonstrated synergistic anti-tumor activity.
• Venetoclax and duvelisib combination significantly inhibited compensatory signaling pathways.
• The combination induced apoptosis in preclinical models of ibrutinib-resistant MCL.

Conclusions:

• The combination of venetoclax and duvelisib represents a potential therapeutic strategy for MCL patients with ibrutinib failure.
• Further clinical trial evaluation of this combination is warranted for patients with relapsed or refractory MCL.