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; Katrine Melhus; Roman Generalov; Sania Gilani; Francesco Bertoni; Jostein Dahle; Randi G Syljuåsen; Sebastian Patzke

doi:10.3389/fonc.2019.01301

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

Front Oncol. 2019 Nov 29:9:1301. doi: 10.3389/fonc.2019.01301. eCollection 2019.

Authors

Gro Elise Rødland¹, Katrine Melhus², Roman Generalov², Sania Gilani¹, Francesco Bertoni³, Jostein Dahle², Randi G Syljuåsen¹, Sebastian Patzke^{1

2}

Affiliations

¹ Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
² Research and Development, Nordic Nanovector ASA, Oslo, Norway.
³ Lymphoma and Genomics Research Program, Institute of Oncology Research, Università Della Svizzera Italiana, Lugano, Switzerland.

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.

Keywords: CD37; aurora kinase; combination therapy; cyclin-dependent kinase; lymphoma; polo-like kinase; radiation resistance; radioimmunotherapy (RIT).