What question did this study set out to answer?

To determine whether dual mTORC1/mTORC2 inhibition enhances the antileukemic efficacy of the BCL2 antagonist venetoclax in acute myelogenous leukemia and to elucidate the underlying molecular mechanisms.

January 18, 2023Clinical Cancer ResearchOpen Access

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

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Authors

TSToshihisa Satta LLLin Li SCSri Lakshmi Chalasani

Discussion

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Overview

Preclinical study reveals that dual mTORC1/2 inhibition combined with venetoclax enhances cell death in acute myelogenous leukemia, suggesting a novel strategy to overcome treatment resistance.

Key Points

To determine whether dual mTORC1/mTORC2 inhibition enhances the antileukemic efficacy of the BCL2 antagonist venetoclax in acute myelogenous leukemia and to elucidate the underlying molecular mechanisms.
Assessed venetoclax and the dual mTORC1/2 inhibitor INK128 in AML cell lines, primary patient samples, and normal CD34+ hematopoietic cells.
Investigated apoptotic mechanisms using cell models with MCL-1 overexpression, constitutively active AKT, BAK/BAX knockouts, and acquired venetoclax resistance.
Evaluated in vivo therapeutic efficacy using AML cell line xenograft and patient-derived xenograft mouse models.
Co-treatment with venetoclax and INK128—but not the mTORC1 inhibitor rapamycin—dramatically increased cell death, an effect mediated by MCL-1 downregulation and BAK/BAX activation.
Synergistic cell death was preserved in venetoclax-resistant AML cells, primary patient samples, and cells with constitutive AKT activation, while sparing normal CD34+ cells.
Combination treatment significantly enhanced antileukemic tumor suppression in both cell line xenograft and patient-derived xenograft models in vivo.

Cite This Study

Satta et al. (2023) studied this question.

synapsesocial.com/papers/6a17e77caeefdf6d9c13210f https://doi.org/10.1158/1078-0432.ccr-22-2729

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January 18, 2023Clinical Cancer ResearchOpen Access

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

View Full Paper

Ask AI

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Authors

TSToshihisa Satta LLLin Li SCSri Lakshmi Chalasani

Discussion

Member takes

Overview

Preclinical study reveals that dual mTORC1/2 inhibition combined with venetoclax enhances cell death in acute myelogenous leukemia, suggesting a novel strategy to overcome treatment resistance.

Key Points

To determine whether dual mTORC1/mTORC2 inhibition enhances the antileukemic efficacy of the BCL2 antagonist venetoclax in acute myelogenous leukemia and to elucidate the underlying molecular mechanisms.
Assessed venetoclax and the dual mTORC1/2 inhibitor INK128 in AML cell lines, primary patient samples, and normal CD34+ hematopoietic cells.
Investigated apoptotic mechanisms using cell models with MCL-1 overexpression, constitutively active AKT, BAK/BAX knockouts, and acquired venetoclax resistance.
Evaluated in vivo therapeutic efficacy using AML cell line xenograft and patient-derived xenograft mouse models.
Co-treatment with venetoclax and INK128—but not the mTORC1 inhibitor rapamycin—dramatically increased cell death, an effect mediated by MCL-1 downregulation and BAK/BAX activation.
Synergistic cell death was preserved in venetoclax-resistant AML cells, primary patient samples, and cells with constitutive AKT activation, while sparing normal CD34+ cells.
Combination treatment significantly enhanced antileukemic tumor suppression in both cell line xenograft and patient-derived xenograft models in vivo.

Cite This Study

Satta et al. (2023) studied this question.

synapsesocial.com/papers/6a17e77caeefdf6d9c13210f https://doi.org/10.1158/1078-0432.ccr-22-2729

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