A novel BCL-2 inhibitor APG-2575 exerts synthetic lethality with BTK or MDM2-P53 inhibitor in Diffuse Large B-Cell Lymphoma.

In this study, our aim is to explore a rational combination of BCL-2 inhibitor plus Bruton's tyrosine kinase (BTK) blockade or p53 activation for treating DLBCL with the above characteristics. We demonstrated that a novel BCL-2 selective inhibitor APG-2575 effectively suppressed DLBCL with BCL-2 high expression via activating the mitochondrial apoptosis pathway. BTK inhibitor ibrutinib combined with BCL-2 inhibitors showed synergistic antitumor effect in DLBCL with mean expression of BCL-2 and myeloid cell leukemia-1 (MCL-1) through upregulating the expression level of BIM and modulating MCL-1 and p-Akt expression. For p53 wild-type DLBCL with high expression of BCL-2, APG-2575 showed strong synergic effect with Mouse double minute 2 (MDM2)-P53 inhibitor APG-115 that can achieve potent anti-tumor effect and markedly prolong survival in animal models. Collectively, our data provides an effective and precise therapeutic strategy through rational combination of BCL-2 and BTK or MDM2-P53 inhibitors for DLBCL, which deserves further clinical investigation. PMID: 32093809 [PubMed - as supplied by publisher]
Source: Oncology Research - Category: Cancer & Oncology Tags: Oncol Res Source Type: research