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- Title
Co-targeting BCL-X<sub>L</sub> and MCL-1 with DT2216 and AZD8055 synergistically inhibit small-cell lung cancer growth without causing on-target toxicities in mice.
- Authors
Khan, Sajid; Kellish, Patrick; Connis, Nick; Thummuri, Dinesh; Wiegand, Janet; Zhang, Peiyi; Zhang, Xuan; Budamagunta, Vivekananda; Hua, Nan; Yang, Yang; De, Umasankar; Jin, Lingtao; Zhang, Weizhou; Zheng, Guangrong; Hromas, Robert; Hann, Christine; Zajac-Kaye, Maria; Kaye, Frederic J.; Zhou, Daohong
- 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-XL 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-XL 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-XL 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-XL/MCL-1 co-dependent SCLC cells, but not normal cells. Mechanistically, the combination caused BCL-XL 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-XL and MCL-1.
- Subjects
TUMOR growth; BCL-2 proteins; LUNG cancer; MICE; MTOR inhibitors; SOFT tissue injuries; PROGRESSION-free survival
- Publication
Cell Death Discovery, 2023, Vol 9, Issue 1, p1
- ISSN
2058-7716
- Publication type
Article
- DOI
10.1038/s41420-022-01296-8