Abstract 411: Selective degradation of SMARCA2 and dual degradation of SMARCA2 and SMARCA4 has strong antitumor activity in marginal zone lymphoma (MZL)

Background: The SWI/SNF chromatin remodeling complex is crucial for normal B cell development. Its importance is underlined by the occurrence of somatic mutations in genes coding for subunits of the complex, such as ARID1A and SMARCA4, in lymphomas. PRT3789 is a novel bifunctional small molecule containing a SMARCA2-bromodomain binder linked to a VHL E3 ubiquitin ligase-binding moiety, with preclinical activity in SMARCA4-deficient cancer cells but not SMARCA4 wt cells. PRT3789 is currently in phase 1 as a single agent or in combination with docetaxel for patients with solid tumors with loss of SMARCA4. Here, we assessed the antitumor activity of the SMARCA2 degrader PRT3789 and a novel dual SMARCA2/4 degrader in MZL preclinical models, including derivatives with acquired resistance to BTK, PI3K, and BCL2 inhibitors. Methods: VL51, Karpas1718, SSK41, ESKOL, HC1, HAIRM and derivatives with resistance to targeted agents obtained by long drug exposure (3 from VL51, 1 from Karpas1718 and SSK41) were exposed to increasing concentrations of the compounds or DMSO, as control. Anti-proliferative activity was assessed by MTT assay after 6 days of exposure. Cell cycle and apoptosis assays were performed. Results: Antitumor activity was seen in the nM range with both compounds. PRT3789 had a median IC50 of 13.27 nM (95%CI, 3.91-41.19). The dual SMARCA2/4 degrader was more active, with a median IC50 of 0.93 nM (95%CI, 0.18-1.92). The activity was maintained in cells with acquired resistance to BTK, PI3K, and BCL2 inhibitors. None of the models had mutations in the coding regions of ARID1A or SMARCA4.Adding individual degraders to the BTK inhibitor ibrutinib, the PI3Kδ inhibitor idelalisib, or to the combination of the PI3K inhibitor copanlisib with the BCL2 inhibitor venetoclax led to additivity/synergism. Adding a low concentration of the degraders (1-10nM) overcame resistance to either copanlisib/venetoclax, ibrutinib, or idelalisib. Adding the dual SMARCA2/4 degrader increased copanlisib/venetoclax efficacy in resistant SSK41 and was strongly synergistic in resistant VL51. Adding PRT3789 enhanced copanlisib/venetoclax and ibrutinib potencies and idelalisib efficacy in the corresponding resistant cells. When we exposed Karpas1718 and SSK41 to the two degraders as single agents or in combination with ibrutinib, we observed that the addition of the compounds improved the cytotoxic activity of ibrutinib in both cell lines by inducing apoptosis. Conclusions: The single SMARCA2 degrader PRT3789 and the dual SMARCA2/4 degrader showed strong dose-dependent cytotoxic activity in MZL cells, showing activity in the low nM range. Both compounds induced apoptosis as single agents and improved the activity of a BTK inhibitor in the two cell lines tested. Interestingly, the antitumor activity was maintained in MZL cell lines with acquired resistance to BTK, PI3K, and BCL2 inhibitors. Citation Format: Alberto J. Arribas, Eleonora Cannas, Stefano Pileri, Davide Rossi, Diane Heiser, Francesco Bertoni. Selective degradation of SMARCA2 and dual degradation of SMARCA2 and SMARCA4 has strong antitumor activity in marginal zone lymphoma (MZL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 411.