Dual mTORC1/2 Inhibition Synergistically Enhances AML Cell Death in Combination with the BCL2 Antagonist Venetoclax

Area of Science:

• Oncology
• Hematology
• Molecular Biology

Background:

• Acute myelogenous leukemia (AML) is an aggressive hematologic malignancy with poor patient outcomes.
• Venetoclax (ABT-199) is a targeted therapy for AML, but resistance mechanisms limit its efficacy.
• Targeting the mTOR pathway presents a potential strategy to enhance venetoclax activity.

Purpose of the Study:

• To investigate the synergistic potential of dual mTORC1/TORC2 inhibition with venetoclax in potentiating anti-AML activity.
• To elucidate the underlying molecular mechanisms of venetoclax and dual mTOR inhibition combination therapy.
• To evaluate the efficacy of this combination in preclinical AML models, including resistant and primary patient samples.

Main Methods:

• In vitro assessment of venetoclax/INK128 (dual mTOR inhibitor) synergism in AML cell lines and primary patient samples.
• Investigation of mechanisms including MCL-1, BAK/BAX, AKT, and 4EBP1 modulation.
• Evaluation in AML models with specific genetic alterations (MCL-1 overexpression, AKT activation, BAK/BAX knockout) and acquired resistance.
• In vivo efficacy studies using xenograft and patient-derived xenograft (PDX) models.

Main Results:

• Combination of venetoclax and INK128 significantly enhanced AML cell death, outperforming rapamycin (mTORC1 inhibitor).
• Synergism was dependent on MCL-1 downregulation and BAK/BAX upregulation, while MCL-1 overexpression or BAX/BAK knockout abrogated cell death.
• Constitutive AKT activation hindered synergism with PI3K/AKT inhibitors but not INK128.
• The combination demonstrated efficacy in venetoclax-resistant AML cells, primary patient samples, and in vivo models.

Conclusions:

• The venetoclax/INK128 regimen exhibits potent antileukemic activity in diverse preclinical AML models.
• Mechanisms involve MCL-1 downregulation and BAK/BAX activation, offering advantages over other inhibitors in specific contexts.
• This combination is effective against primary and resistant AML, warranting further clinical investigation.