Back to Search
Start Over
Co-targeting BCL-X L and MCL-1 with DT2216 and AZD8055 synergistically inhibit small-cell lung cancer growth without causing on-target toxicities in mice.
- Source :
-
Cell death discovery [Cell Death Discov] 2023 Jan 02; Vol. 9 (1), pp. 1. Date of Electronic Publication: 2023 Jan 02. - Publication Year :
- 2023
-
Abstract
- Small-cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. The dismal prognosis in SCLC is in part associated with an upregulation of BCL-2 family anti-apoptotic proteins, including BCL-X <subscript>L</subscript> and MCL-1. Unfortunately, the currently available inhibitors of BCL-2 family anti-apoptotic proteins, except BCL-2 inhibitors, are not clinically relevant because of various on-target toxicities. We, therefore, aimed to develop an effective and safe strategy targeting these anti-apoptotic proteins with DT2216 (our platelet-sparing BCL-X <subscript>L</subscript> degrader) and AZD8055 (an mTOR inhibitor) to avoid associated on-target toxicities while synergistically optimizing tumor response. Through BH3 mimetic screening, we identified a subset of SCLC cell lines that is co-dependent on BCL-X <subscript>L</subscript> and MCL-1. After screening inhibitors of selected tumorigenic pathways, we found that AZD8055 selectively downregulates MCL-1 in SCLC cells and its combination with DT2216 synergistically killed BCL-X <subscript>L</subscript> /MCL-1 co-dependent SCLC cells, but not normal cells. Mechanistically, the combination caused BCL-X <subscript>L</subscript> degradation and suppression of MCL-1 expression, and thus disrupted MCL-1 interaction with BIM leading to an enhanced apoptotic induction. In vivo, the DT2216 + AZD8055 combination significantly inhibited the growth of cell line-derived and patient-derived xenografts and reduced tumor burden accompanied by increased survival in a genetically engineered mouse model of SCLC without causing appreciable thrombocytopenia or other normal tissue injuries. Thus, these preclinical findings lay a strong foundation for future clinical studies to test DT2216 + mTOR inhibitor combinations in a subset of SCLC patients whose tumors are co-driven by BCL-X <subscript>L</subscript> and MCL-1.<br /> (© 2023. The Author(s).)
Details
- Language :
- English
- ISSN :
- 2058-7716
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell death discovery
- Publication Type :
- Academic Journal
- Accession number :
- 36588105
- Full Text :
- https://doi.org/10.1038/s41420-022-01296-8