NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263

• Published in: Clinical cancer research Vol. 25; no. 1; pp. 312 - 324
• Main Authors: Dastur, Anahita, Choi, AHyun, Costa, Carlotta, Yin, Xunqin, Williams, August, McClanaghan, Joseph, Greenberg, Max, Roderick, Justine, Patel, Neha U, Boisvert, Jessica, McDermott, Ultan, Garnett, Mathew J, Almenara, Jorge, Grant, Steven, Rizzo, Kathryn, Engelman, Jeffrey A, Kelliher, Michelle, Faber, Anthony C, Benes, Cyril H
• Format: Journal Article
• Language: English
• Published: United States 01.01.2019
• Subjects: Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - genetics; Aniline Compounds - pharmacology; Animals; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Heterografts; Humans; Mechanistic Target of Rapamycin Complex 1 - genetics; Mice; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Receptor, Notch1 - genetics; Signal Transduction - drug effects; Sulfonamides - pharmacology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-0867

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. 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 experiments and studies on patient-derived xenograft models. 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 and leads to tumor regressions . 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.