The first-in-class WASP activator EG-011 is active in lymphoma and multiple myeloma cell lines resistant to FDA approved compounds

Background: One of the major causes failure to achieve cure in cancer patients is development resistance drugs after an initial response. EG-011 first-in-class Wiskott-Aldrich syndrome protein (WASP) activator (Spriano et al, AACR 2022) with anti-tumor activity hematological cancers (Gaudio 2019). Here, we assessed context cellular models secondary FDA approved agents: marginal zone lymphoma (MZL) cell lines resistant PI3K and BTK inhibitors multiple myeloma (MM) proteasome inhibitors. Methods: MZL MM were exposed a large range concentrations as single agent for 72 h, followed by MTT 4 h SDS stop reaction. The day after, plates read using Cytation 3 multimode plate reader (Biotek) IC50s calculated. IC50 was defined drug concentration giving 50% proliferating cells compared vehicle treated cells. Results: We first tested from splenic (Arribas ASH 2019, ENA 2020, Haematologica 2022). maintained line derived VL51 ibrutinib (IC50: 500 nM both parental resistant), while it higher model PI3Kdelta inhibitor 100 nM). copanlisib-resistant 2 μM) Karpas1718 idelalisib-resistant (5 nM) showed slightly decreased sensitivity (Karpas1718 parental, IC50: 1 then lack cross acquired this class agents (Besse Leukemia 2018, 2019; Brünnert BBA Mol Basis Dis AMO-1 carfilzomib treatment that more than 20 times lower sensitive 250 vs 6 μM). L363 bortezomib around ten 12 A 4-fold increase observed RPMI-8266 2.5 10 μM models). Conclusions: These data indicate WASP active also acquisition different such PI3K, models. Conflict interest: Ownership: Patent