TARGETED DNA DAMAGE BOOST WITH LONCASTUXIMAB TESIRINE IN COMBINATION WITH PARP INHIBITORS IN DIFFUSE LARGE B-CELL LYMPHOMA

Overexpression of the MYC oncogene is a key event in lymphomagenesis and a frequent characteristic of refractory Diffuse Large B Cell Lymphoma (DLBCL); MYC overexpression leads to genomic instability and inherent DNA damage, which is attenuated by several mechanisms including constitutive activation of DNA damage response (DDR) pathway. In addition, MYC-driven cancers frequently overexpress PARP-1, relying on its activity to attenuate endogenous replicative stress. This evidence prompted us to target DDR with PARP inhibitors as synthetic lethal therapeutic strategy for MYC-driven DLBCL. Antibody-drug conjugates bind antigens expressed on the surface of cancer cells and specifically transfer cytotoxic payloads. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate directed against CD19 which causes DNA damage by delivering a DNA crosslink-inducing pyrrolobenzodiazepine dimer into target B-cells. With the purpose of enhancing Lonca-mediated DNA damage induction, in this project we tested the specific PARP-1 inhibitor Talazoparib in combination with Lonca in a panel of DLBCL cell lines. Loncastuximab/Talazoparib combination showed significant anti-lymphoma activity in most of DLBCL cell lines irrespective of MYC/BCL2 rearrangements or TP53 mutational status. The BRCA2-mutated cell line Dohh2 showed the highest sensitivity to PARP inhibition in line with the well-known synthetic lethality between BRCA mutations and PARP inhibition. Lonca/Talazoparib combination resulted in specific changes in cell cycle dynamics such as an increased fraction of cells arrested in S phase, suggesting a mechanistic interaction between the two compounds. RNA-Seq analysis resulted in specific gene expression profile changes such as downregulation of Aurora Kinase A, which is involved in S and G2/M transition of cell cycle. Similar results were obtained replacing Loncastuximab with a different crosslinking agent, cisplatin, indicating a class effect. Notably, Lonca and Talazoparib as single agents or in combination did not determine significant DNA damage on healthy T cells. In line with its mechanism of action, Lonca determined detectable DNA damage in healthy B cells, which was not enhanced by the addition of Talazoparib. The synergistic interaction between Lonca and Talazoparib was further confirmed in vivo in a MYC/BCL2 double hit PDX model with a significant reduction in tumor growth associated with increased overall survival. These data provide the rationale for future therapeutic strategies based on selective induction of DNA damage in neoplastic B cells in combination with DDR inhibition in aggressive B cell lymphoma.