Abstract C144: MEN1703/SEL24, a potent PIM inhibitor, demonstrates promising anti-tumour activity in activated B cell like diffuse large B cell lymphoma, mantle cell lymphoma and marginal zone lymphoma cells

Abstract

Abstract Background. PIM kinases (PIM1, PIM2, PIM3) are serine threonine kinases that function in multiple biological processes including cell cycle regulation, cell survival and proliferation. They also mediate resistance to anti-tumour agents comprising PI3K inhibitors. PIM1 overexpression and mutations are common in diffuse large B cell lymphoma (DLBCL) and PIM1 overexpression has been validated as a rational therapeutic target particularly in ABC and MCD subtypes. PIM1 overexpression is also found in mantle cell lymphoma (MCL). We investigated the pharmacological inhibition of PIM using the small molecule MEN1703/SEL24 in a large panel of lymphoma cell lines. Methods. Anti-proliferative activity was assessed by MTT assay at 72h: MEN1703/SEL24 was tested in 7 ABC-DLBCL, 19 germinal centre-B cell-like (GCB)-DLBCL, nine MCL, six marginal zone lymphoma (MZL), one primary mediastinal, four MZL ibrutinib-and PI3K-resistant models and one canine lymphoma. Cell cycle and apoptosis assays were done by flow cytometry. RNA-Seq was performed on two ABC- and two GCB-DLBCL cell lines treated with MEN1703/SEL24 or DMSO for 4, 8, 12h, followed by limma and functional annotation analysis with gene set enrichment analysis (GSEA). Results. MEN1703/SEL24 showed anti-proliferative activity in all lymphoma histotypes tested (IC50 median = 593 nM; range = 30 - 10,193 nM). MCL (IC50 median = 108 nM; range = 53 - 412 nM) and ABC-DLBCL (IC50median = 994 nM; range = 30 - 1756 nM) were the most sensitive histotypes; among them OCI-Ly-10 (30 nM) and OCI-Ly-3 (142 nM) had mutated PIM1. GCB-DLBCLs comprised the least sensitive cell lines (IC50 median = 961 nM; range = 252 - 10,193 nM) accounting for 8/11 cell lines with IC50 in the upper percentile. More importantly, MEN1703/SEL24 was active in MZL cell lines with acquired resistance to idelalisib, copanlisib and ibrutinib (IC50 median = 367 nM; range = 273 - 410 nM). MEN1703/SEL24 induced apoptosis in 6/6 cell lines and minor G1 arrest in 1/6 cell lines. In DLBCL cell lines more sensitive to MEN1703/SEL24 treatment, RNA-Seq and GSEA revealed differential modulation of immune, MYC and E2F targets. Conclusions. MEN1703/SEL24 shows robust preclinical activity in B cell lymphomas of different histotypes. RNA-Seq indicates that MEN1703/SEL24 modulates the transcriptome of highly responsive DLBCL cell lines differently from poorly responsive cells, providing novel clues to mechanisms involved in sensitivity to PIM inhibitors and supporting a potential for clinical development in this indication. Citation Format: Afua A. Mensah, Alessandro Ghiringhelli, Giulio Sartori, Filippo Spriano, Chiara Tarantelli, Luciano Cascione, Andrea Rinaldi, Alberto A. Arribas, Daniela Bellarosa, Monica Binaschi, Francesco Bertoni. MEN1703/SEL24, a potent PIM inhibitor, demonstrates promising anti-tumour activity in activated B cell like diffuse large B cell lymphoma, mantle cell lymphoma and marginal zone lymphoma cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C144.