Bcl-2 family inhibitors sensitize human cancer models to target therapy

Abstract

AbstractBH3 mimetics, targeting Bcl-2 family anti-apoptotic proteins, represent a promising therapeutic opportunity in tumors. ABT-199, the first specific Bcl-2 inhibitor, has been approved by FDA for treating several hematological malignancies. We have recently discovered IS21, a novel pan BH3 mimetic with preclinical anti-tumor activity in different cancers. This study aimed to evaluate the efficacy of different BH3 mimetics both as single agents, in a panel of different tumor cell histotypes, and in combination with the currently used target therapy in ovarian cancer and melanoma. Our results demonstrate that IS21 reduced the viability of T-cell acute lymphoblastic leukemia, melanoma, lung, pancreatic and ovarian cancer cell lines, and that Bcl-xL and Mcl-1 protein levels were markers of IS21 sensitivity in melanoma and ovarian cancer, respectively. Exploring the IS21 mechanism of action, we reported that IS21 activity was dependent on BAX and BAK proteins, and complexes between Bcl-2 and Bcl-xL proteins and their main binding partners were reduced by IS21. In combination experiments, BH3 mimetics sensitized ovarian cancer cells to the treatment with PARP inhibitors, while IS21 and ABT-199 synergized with MAPK inhibitors in melanoma models bothin vitroandin vivo.Through different methodological approaches, we evidenced that the potentiating effect of BH3 mimetics was related to enhancement of apoptotic pathway, both in melanoma and ovarian cancer. In conclusion, our data suggest the use of inhibitors of the anti-apoptotic proteins as a possible therapeutic strategy to enhance the efficacy of target therapy in ovarian cancer and melanoma.