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Bak and Bcl-xL Participate in Regulating Sensitivity of Solid Tumor Derived Cell Lines to Mcl-1 Inhibitors
Viacheslav V Senichkin1, Nikolay V Pervushin1, Alexey V Zamaraev1
1Faculty of Medicine, MV Lomonosov Moscow State University, 119991 Moscow, Russia.
Abstract:
BH3 mimetics represent a promising tool in cancer treatment. Recently, the drugs targeting the Mcl-1 protein progressed into clinical trials, and numerous studies are focused on the investigation of their activity in various preclinical models. We investigated two BH3 mimetics to Mcl-1, A1210477 and S63845, and found their different efficacies in on-target doses, despite the fact that both agents interacted with the target. Thus, S63845 induced apoptosis more effectively through a Bak-dependent mechanism. There was an increase in the level of Bcl-xL protein in cells with acquired resistance to Mcl-1 inhibition. Cell lines sensitive to S63845 demonstrated low expression of Bcl-xL. Tumor tissues from patients with lung adenocarcinoma were characterized by decreased Bcl-xL and increased Bak levels of both mRNA and proteins. Concomitant inhibition of Bcl-xL and Mcl-1 demonstrated dramatic cytotoxicity in six of seven studied cell lines. We proposed that co-targeting Bcl-xL and Mcl-1 might lead to a release of Bak, which cannot be neutralized by other anti-apoptotic proteins. Surprisingly, in Bak-knockout cells, inhibition of Mcl-1 and Bcl-xL still resulted in pronounced cell death, arguing against a sole role of Bak in the studied phenomenon. We demonstrate that Bak and Bcl-xL are co-factors for, respectively, sensitivity and resistance to Mcl-1 inhibition.
Insights
BH3 mimetics targeting Mcl-1 show varied efficacy. Co-inhibition of Bcl-xL and Mcl-1 enhances cancer cell death, with Bak and Bcl-xL acting as key factors in Mcl-1 inhibitor response.
Area of Science:
- Molecular Oncology
- Cancer Therapeutics
Background:
- BH3 mimetics targeting Mcl-1 are emerging cancer therapeutics.
- Understanding resistance mechanisms is crucial for optimizing Mcl-1 inhibitor efficacy.
Purpose of the Study:
- To compare the efficacy of two Mcl-1 inhibitors, A1210477 and S63845.
- To investigate the roles of Bak and Bcl-xL in Mcl-1 inhibitor response and resistance.
- To evaluate the potential of combined Bcl-xL and Mcl-1 inhibition in cancer treatment.
Main Methods:
- Investigated two Mcl-1 targeting BH3 mimetics (A1210477, S63845) in preclinical cancer models.
- Analyzed protein and mRNA levels of Bak and Bcl-xL in sensitive and resistant cell lines.
- Assessed cytotoxicity of combined Bcl-xL and Mcl-1 inhibition in various cell lines, including Bak-knockout models.
Main Results:
- S63845 demonstrated greater apoptosis induction via a Bak-dependent pathway compared to A1210477.
- Acquired resistance to Mcl-1 inhibition correlated with increased Bcl-xL levels.
- Combined inhibition of Bcl-xL and Mcl-1 induced significant cytotoxicity across multiple cell lines.
- Bak and Bcl-xL were identified as co-factors for sensitivity and resistance to Mcl-1 inhibition, respectively.
Conclusions:
- Bak and Bcl-xL play critical roles in modulating cellular response to Mcl-1 inhibition.
- Co-targeting Bcl-xL and Mcl-1 represents a promising strategy for overcoming resistance and enhancing anti-cancer effects.
- The interplay between Bak, Bcl-xL, and Mcl-1 offers novel therapeutic avenues in cancer treatment.
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