Improving responses to dual PI3K/BCL2 inhibition in lymphomas: results of a pharmacological screen with over 1,400 compounds

Background: Copanlisib, a pan-PI3K inhibitor with stronger activity against the alpha and delta isoforms, is Food Drug Administration (FDA) approved for treatment of patients relapsed or refractory follicular lymphoma, it has shown clinical in other indolent lymphomas including marginal zone lymphoma (MZL). Preclinical studies have demonstrated strong synergism copanlisib BCL2 venetoclax different (Tarantelli Blood Adv 2020). A phase 1 study explored this specific combination (NCT03886649), while others similar schemes based on dual PI3K targeting. We previously reported model resistance to copanlisib/venetoclax developed by prolonged exposure (Arribas ENA Here, we present data from large pharmacological screen over 1400 compounds MZL model. Methods: Copanlisib/venetoclax-resistant cells were exposed DMSO library 1443 FDA-approved at 5 μM dose, as single nM +50 72 hours (hr). Spatial intra- inter-plates effects corrected. Values then normalized control (DMSO). Either highly active agent (cell viability <30%) inhibitors improved upon copanlisib/ <50%, ratio combo/single <0.7) selected further validation resistant parental (MTT assay, hr). Synergy combinations was evaluated according Chou-Talalay index (CI), well potency efficacy, estimated MuSyC algorithm. Results: The identified 82 99 drugs that response copanlisib/venetoclax. These targeted WNT, CDK, HDAC, HSP, PLK, ALDH1, AURKA, proton pump microtubule polymerization, among others. selection underwent experiments combination. Addition ALDH1 disulfiram beneficial both cells, but especially latter condition synergy enhanced efficacy venetoclax, overcoming resistance. Combinations ganetespib (HSP90), rigosertib (PLK), panobinostat (HDAC), alisertib (AURKA) AZ1602 (WNT) either sensitivity cells. Conclusions: In conclusion, series could be added triple used developing Further are on-going extend findings additional PI3K/BCL2 inhibitors. Work partially supported Swiss Cancer Research. No conflict interest.