Abstract
Soft tissue sarcomas (STS) are a heterogeneous group of malignancies predominantly affecting children and young adults. Despite improvements in multimodal therapies, 5-year survival rates are only 50% and new treatment options in STS are urgently needed. To develop a rational combination therapy for the treatment of STS we focused on ABT-199 (Venetoclax), a BCL-2 specific BH3-mimetic, in combination with the proteasome inhibitor bortezomib (BZB). Simultaneous inhibition of BCL-2 and the proteasome resulted in strongly synergistic apoptosis induction. Mechanistically, ABT-199 mainly affected the multidomain effector BAX by liberating it from BCL-2 inhibition. The combination with BZB additionally resulted in the accumulation of BOK, a BAX/BAK homologue, and of the BH3-only protein NOXA, which inhibits the anti-apoptotic protein MCL-1. Thus, the combination of ABT-199 and BZB sensitizes STS cells to apoptosis by simultaneously releasing several defined apoptotic restraints. This synergistic mechanism of action was verified by CRISPR/Cas9 knock-out, showing that both BAX and NOXA are crucial for ABT-199/BZB-induced apoptosis. Noteworthy, efficient induction of apoptosis by ABT-199/BZB was not affected by the p53 status and invariably detected in cell lines and patient-derived tumor cells of several sarcoma types, including rhabdomyo-, leiomyo-, lipo-, chondro-, osteo-, or synovial sarcomas. Hence, we propose the combination of ABT-199 and BZB as a promising strategy for the treatment of STS, which should warrant further clinical investigation.
Highlights
Soft tissue sarcomas (STS) comprise a heterogeneous group of malignancies of mesenchymal origin with more than 100 different histologic subtypes and entities[1]
BCL-2 addicted cells are prone to apoptosis induction by small-molecule inhibitors of anti-apoptotic BCL-2 proteins, such as ABT-19931
Because expression of the BH3-only protein NOXA as well as the proapoptotic effector BOK22 is enhanced by proteasome inhibition, we hypothesized that reducing the antiapoptotic capacity by ABT-199 and simultaneously enhancing the pro-apoptotic activity of NOXA and BOK by the proteasome inhibitor BZB might be a rational strategy in STS
Summary
Soft tissue sarcomas (STS) comprise a heterogeneous group of malignancies of mesenchymal origin with more than 100 different histologic subtypes and entities[1]. Due to the genetic heterogeneity of STS, especially in a metastatic disease, therapeutic options are limited and the average 5-year survival rate, regardless of the type of sarcoma, is only 50%3. Muenchow et al Cell Death and Disease (2020)11:701 chemotherapeutic treatment option especially for young patients is doxorubicin that shows a rather steep doseresponse curve[4]. The 5-year survival rate was only marginally affected[5] and, due to its high toxicity, doxorubicin in combination with ifosfamide is a rational treatment option only in young and fit patients. Efficacy of vorinostat in the treatment of sarcoma has been tested together with the proteasome inhibitor bortezomib (BZB), but despite good tolerability patients did not respond in a clinical phase II trial[7]. Efficient treatment of sarcomas still remains an unmet clinical need[10]
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