Autophagy controls everolimus (RAD001) activity in mantle cell lymphoma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Mantle cell lymphoma (MCL) is an aggressive hematological malignancy with limited effective treatment options.
• The mechanistic target of rapamycin (MTOR) kinase inhibitor everolimus shows preclinical and clinical activity in MCL, but its precise mechanism is not fully understood.
• Understanding resistance mechanisms is crucial for developing more effective MCL therapies.

Purpose of the Study:

• To elucidate the mechanism of action of everolimus in MCL cells.
• To investigate the potential of combining MTOR and AKT inhibition for MCL treatment.
• To identify strategies to overcome resistance to dual AKT-MTOR targeting.

Main Methods:

• Mantle cell lymphoma cell lines and primary samples were treated with everolimus and a selective AKT inhibitor.
• Phosphorylation status of AKT was monitored.
• Autophagic vacuoles were assessed.
• ATG gene knockdown and hydroxychloroquine were used to inhibit autophagy.
• Cell viability and efficacy were evaluated.

Main Results:

• Everolimus activity in MCL cells correlates with AKT phosphorylation status.
• Combining everolimus with a selective AKT inhibitor enhances anti-lymphoma activity.
• Accumulation of autophagic vacuoles is associated with resistance to dual AKT-MTOR inhibition.
• Autophagy inhibition, via ATG gene knockdown or hydroxychloroquine, restores sensitivity to dual therapy.
• This triple combination strategy demonstrates efficacy in MCL cell lines and primary samples.

Conclusions:

• Autophagy plays a prosurvival role in AKT-MTOR compromised MCL cells.
• Inhibiting autophagy can overcome resistance to combined MTOR and AKT inhibitors in MCL.
• A triple combination strategy involving MTOR inhibitors, AKT inhibitors, and autophagy inhibitors shows therapeutic potential for hematological malignancies like MCL.