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NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263
Anahita Dastur1, AHyun Choi2, Carlotta Costa1
1Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
Purpose:
Effective targeted therapies are lacking for refractory and relapsed T-cell acute lymphoblastic leukemia (T-ALL). Suppression of the NOTCH pathway using gamma-secretase inhibitors (GSI) is toxic and clinically not effective. The goal of this study was to identify alternative therapeutic strategies for T-ALL.
Experimental Design:
We performed a comprehensive analysis of our high-throughput drug screen across hundreds of human cell lines including 15 T-ALL models. We validated and further studied the top hit, navitoclax (ABT-263). We used multiple human T-ALL cell lines as well as primary patient samples, and performed both in vitro experiments and in vivo studies on patient-derived xenograft models.
Results:
We found that T-ALL are hypersensitive to navitoclax, an inhibitor of BCL2 family of antiapoptotic proteins. Importantly, GSI-resistant T-ALL are also susceptible to navitoclax. Sensitivity to navitoclax is due to low levels of MCL-1 in T-ALL. We identify an unsuspected regulation of mTORC1 by the NOTCH pathway, resulting in increased MCL-1 upon GSI treatment. Finally, we show that pharmacologic inhibition of mTORC1 lowers MCL-1 levels and further sensitizes cells to navitoclax in vitro and leads to tumor regressions in vivo.
Conclusions:
Our results support the development of navitoclax, as single agent and in combination with mTOR inhibitors, as a new therapeutic strategy for T-ALL, including in the setting of GSI resistance.
Insights
Navitoclax shows promise as a targeted therapy for T-cell acute lymphoblastic leukemia (T-ALL), even in cases resistant to gamma-secretase inhibitors (GSI). Combining navitoclax with mTOR inhibitors offers a potential new treatment strategy for T-ALL.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Targeted therapies for refractory and relapsed T-cell acute lymphoblastic leukemia (T-ALL) are limited.
- Current NOTCH pathway inhibition with gamma-secretase inhibitors (GSI) lacks efficacy and has significant toxicity.
Purpose of the Study:
- To identify alternative therapeutic strategies for T-cell acute lymphoblastic leukemia (T-ALL).
- To investigate the efficacy of navitoclax (ABT-263) as a potential treatment for T-ALL.
Main Methods:
- High-throughput drug screening across hundreds of human cell lines, including T-ALL models.
- In vitro and in vivo studies using human T-ALL cell lines, primary patient samples, and patient-derived xenograft models.
- Analysis of BCL2 family protein expression, particularly MCL-1, and its regulation by the NOTCH and mTORC1 pathways.
Main Results:
- T-ALL cell lines exhibit hypersensitivity to navitoclax, a BCL2 family inhibitor.
- Navitoclax is effective even in GSI-resistant T-ALL, due to low MCL-1 levels.
- NOTCH pathway regulates mTORC1, influencing MCL-1 levels; mTORC1 inhibition sensitizes T-ALL to navitoclax and promotes tumor regression in vivo.
Conclusions:
- Navitoclax demonstrates potential as a single agent or in combination with mTOR inhibitors for T-ALL treatment.
- This strategy is effective even for GSI-resistant T-ALL.
- Further development of navitoclax and mTOR inhibitors is warranted for T-ALL therapy.
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