The Dual Cell Cycle Kinase Inhibitor JNJ-7706621 Reverses Resistance to CD37-Targeted Radioimmunotherapy in Activated B Cell Like Diffuse Large B Cell Lymphoma Cell Lines.

Gro Elise Rødland,Sania Gilani,Randi G Syljuåsen,Roman Generalov,Francesco Bertoni,Katrine Melhus,Sebastian Patzke,Jostein Dahle

doi:10.3389/fonc.2019.01301

Abstract

The CD37 targeting radioimmunoconjugate 177Lu-lilotomab satetraxetan (Betalutin) is currently being evaluated in a clinical phase 2b trial for patients with follicular lymphoma (FL) and in a phase 1 trial for patients with diffuse large B-cell lymphoma (DLBCL). Herein we have investigated the effect of 177Lu-lilotomab satetraxetan in seven activated B-cell like (ABC) DLBCL cell lines. Although the radioimmunoconjugate showed anti-tumor activity, primary resistance was observed in a subset of cell lines. Thus, we set out to identify drugs able to overcome the resistance to 177Lu-lilotomab satetraxetan in two resistant ABC-DLBCL cell lines. We performed a viability-based screen combining 177Lu-lilotomab satetraxetan with the 384-compound Cambridge Cancer Compound Library. Drug combinations were scored using Bliss and Chou-Talalay algorithms. We identified and characterized the dual-specific CDK1/2 and AURA/B kinase inhibitor JNJ-7706621 as compound able to revert the resistance to RIT, alongside topoisomerase and histone deacetylases (HDAC) inhibitors.

Highlights

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, accounting for ∼35% of all newly diagnosed cases
We initially investigated the sensitivity of seven different ABCDLBCL cell lines (HBL1, OciLy-3, Oci-Ly10, RIVA [RI-1], SUDHL-2, TMD-8, U-2932) to treatment with 177Lu-lilotomab satetraxetan
RIVA cells were more sensitive to 177Lulilotomab satetraxetan than U-2932 and showed about 60% of the proliferation capacity of control cells at a dose of 0.5 μg/ml, which is half of the dose required in U-2932 cells to reach a similar level of inhibition

Summary

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, accounting for ∼35% of all newly diagnosed cases. Despite its phenotypical relatively homogenous appearance, DLBCL is a heterogeneous diseases [1]. The most commonly used sub-classification is based on the cell-of-origin (COO), identifying the germinal center B-cell (GCB)-type and the activated B-cell (ABC)-like DLBCL subtypes on the basis of gene or protein expression pattern reminiscent of normal germinal center or ABCs, respectively. Despite the major improvements in our understanding of the biology of DLBCL and the availability of a large number of novel compounds, no new regimen has shown superiority to R-CHOP [2,3,4]. Recent studies have uncovered a high degree of genetic

Methods

Results

Conclusion