Bak and Bcl-xL Participate in Regulating Sensitivity of Solid Tumor Derived Cell Lines to Mcl-1 Inhibitors

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.

A novel MDM2-p53 antagonist APG115 exerts synergistic effect with ibrutinib via targeting MCL-1 in chronic lymphocytic leukemia

“…Similarly, APG115 can synergistically promote apoptosis of ibrutinib by promoting MCL-1 degradation 45,47,48 . The current potential application direction of APG115 is cooperating with cancer immunotherapy.…”

“…P53 binds to MCL-1 and promotes ubiquitination, which is then transferred to proteasome degradation. The decreased expression of MCL-1 promotes apoptosis by up-regulating downstream apoptotic molecules PUMA and NOXA [43][44][45] . Additionally, the PUMA and NOXA further enhances the functions of the pro-apoptotic proteins BAX and BAK.…”

Involvement of Bcl-2 Family Proteins in Tetraploidization-Related Senescence

“…However, free Bak can be recaptured by Bcl-xL, leading to a resistance to A1210477 [ 115 ]. Similarly, S63845-induced apoptosis occurs in a Bak-dependent manner in solid tumor-derived cell lines [ 116 ]. S64315 enhances the selective senolytic effect of ABT-263 and ABT-737.…”

B-cell lymphoma 2 family members and sarcomas: a promising target in a heterogeneous disease

“…Still, in the same study, the authors translated those findings to animal models, in which they found that the addition of the Bcl-xL inhibitor to 5-FU caused the strongest anti-tumoral effect, proving support for association therapies. Several studies with a focus in tumor cells state that a Bcl-xL inhibitor as a single agent is not adequate to promote apoptosis [39]. There are reports in cancer cells and animal models, that the use of BTSA1.2 (an orally bioavailable Bax activator) in combination with Bcl-xL has a synergist anti-tumoral effect while being safe for healthy tissues [39,40].…”

“…Several studies with a focus in tumor cells state that a Bcl-xL inhibitor as a single agent is not adequate to promote apoptosis [39]. There are reports in cancer cells and animal models, that the use of BTSA1.2 (an orally bioavailable Bax activator) in combination with Bcl-xL has a synergist anti-tumoral effect while being safe for healthy tissues [39,40]. This mechanism in which solid tumors rely on Bcl-xL for survival has led to several studies focusing on selective Bcl-xL inhibitors [41].…”