Abstract 939: The combination of liposomal Bcl-2 antisense oligonucleotide (BP1002) with decitabine is efficacious in venetoclax-resistant cells

Background: B-cell lymphoma 2 (Bcl-2) is an oncoprotein that promotes tumor cell survival and drug resistance. Elevated Bcl-2 expression in numerous human cancers has made it an ideal drug target. Venetoclax, the first FDA approved Bcl-2 inhibitor, is indicated for hematologic malignancies. Accompanying its promising clinical results, however, is the emergence of venetoclax resistance. A recent study found that AML patients who had relapsed from frontline venetoclax-based treatment were refractory to salvage therapy and had a median survival of less than 3 months. Thus, novel treatment approaches for such patients are urgently needed. BP1002, a non-toxic neutral dioleoylphosphatidylcholine liposome incorporating a nuclease-resistant P-ethoxy antisense oligonucleotide (oligo), was developed to target Bcl-2 mRNA. The safety and efficacy of BP1002 is being investigated in patients with advanced lymphoid malignancies. Venetoclax in combination with decitabine is an approved treatment for elderly AML patients. Here we determine the effects of BP1002 plus decitabine in venetoclax-resistant cells. Methods: Cell lines: Venetoclax-resistant hematologic cell lines, MV-4-11- R, SU-DHL-2-R, SU-DHL-6-R, were established from the parental cells by exposing the cells to increasing doses of venetoclax for 10-12 weeks.BP1002: A Bcl-2 antisense oligo, which targets the translation initiation site of human Bcl-2 mRNA, was incorporated in BP1002. Combination study: Parental and venetoclax-resistant cells were treated with decitabine for 2 days followed by the addition of BP1002 for another 4 days of incubation. Resazurin-based cell viability assays and Western blots were conducted to determine the inhibitory effects of BP1002 in parental and resistant cells. Results: The IC50 values of venetoclax in resistant cells were 3 to 40 times higher than those in parental cells. MV-4-11-R, SU-DHL-6-R, SU-DHL-2-R cells are resistant up to 0.1 μM, 0.8 μM, and 7 μM venetoclax, respectively. Compared to parental cells, venetoclax-resistant cells displayed 2- to 3-fold elevated levels of Bcl-2 protein and other anti-apoptotic proteins such as Mcl-1. BP1002 in combination with decitabine decreased the viability of parental cells. BP1002 reduced Bcl-2 levels in venetoclax-resistant cells. Also, the BP1002 plus decitabine combination was more potent than the venetoclax plus decitabine combination in reducing the viability of the resistant cells, by about 50-70%. Conclusions: Our data indicate that, despite expressing higher levels of anti-apoptotic proteins, venetoclax-resistant cells are sensitive to the BP1002 plus decitabine combination. These promising preclinical results suggest that the BP1002 plus decitabine combination is a potential treatment for patients who have relapsed from frontline venetoclax-based therapies. Citation Format: Maria Gagliardi, Ana Tari Ashizawa. The combination of liposomal Bcl-2 antisense oligonucleotide (BP1002) with decitabine is efficacious in venetoclax-resistant cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 939.