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 being evaluated as monotherapy 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), as well as in a phase 1b trial in combination with rituximab for patients with relapsed/refractory FL. 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: U-2932 and RIVA. Both cell lines are representative for TP53 deficient Double Expressor (DE) DLBCL. Importantly, resistance was not a consequence of reduced binding of the radioimmunoconjugate to cell surface expressed CD37. Thus, we set out to identify drugs able to overcome the resistance to ¹⁷⁷Lu-lilotomab satetraxetan in both 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 radioimmunotherapy (RIT), alongside topoisomerase and histone deacetylases (HDAC) inhibitors.

Kinetic studies of the effect of mono- and combination therapy of U-2932 and RIVA cells with JNJ-7706621 and ¹⁷⁷Lu-lilotomab satetraxetan are suggestive of a model in which radiation damage induced G₂-arrested lymphoma cells eventually enter mitosis (repair or escape) and mitotic entry, progression and exit are impaired by JNJ-7706621 mediated inhibition of CDK1/2 and AURKA/B. Extended residence-time of cells in mitosis due to chromosome condensation and congression defects as well as spindle and mid-spindle assembly failure is likely pivotal for the increased sensitivity to persistent ¹⁷⁷Lu-lilotomab satetraxetan deposited DNA damage, ultimately promoting cytokinesis failure (multinucleation, aneuploidy, increased cell size) and cell death.

In conclusion, CD37-targeting ¹⁷⁷Lu-lilotomab satetraxetan RIT showed activity in several ABC-DLBCL lymphoma cell lines. CD37-independent RIT-resistance was identified in two cell lines representative of aggressive DE ABC-DLBCLs with inactive TP53, and reversed by subsequent inhibition of CDK1/2 and AURKA/B by JNJ-7706621. These findings may be of potential relevance for ongoing clinical trials of ¹⁷⁷Lu-lilotomab satetraxetan in relapsed, ASCT-non-eligible DLBCL, and may also be more generally applicable to other ¹⁷⁷Lu-based RITs and alternative radionuclide utilizing targeted therapies. Future pre-clinical investigations are required to elucidate the potential application of CDK1/2 and AURKA/B inhibitors as a strategy to revert RIT resistance in TP53 deficient cancers.