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

The CD37-targeting radioimmunoconjugate 177Lu-lilotomab satetraxetan (Betalutin) is currently undergoing clinical evaluation in a phase 2b trial for follicular lymphoma and a phase 1 trial for diffuse large B-cell lymphoma (DLBCL). In this study, we investigated the effect of 177Lu-lilotomab satetraxetan in seven activated B-cell-like (ABC) DLBCL cell lines.

While the radioimmunoconjugate demonstrated anti-tumor activity overall, a subset of the cell lines exhibited primary resistance. To overcome this resistance in two resistant ABC-DLBCL cell lines, we performed a viability-based screen combining 177Lu-lilotomab satetraxetan with compounds from the 384-compound Cambridge Cancer Compound Library.

Drug combinations were evaluated using both the Bliss and Chou-Talalay algorithms. Our screen identified the dual-specific CDK1/2 and AURA/B kinase inhibitor JNJ-7706621 as a compound capable of reversing resistance to radioimmunotherapy. In addition, topoisomerase and histone deacetylase (HDAC) inhibitors were also found to have a similar effect in overcoming resistance.