Orally available decitabine prodrug OR-2100 induces mitotic perturbation for the treatment of double-hit lymphoma

Abstract

Double-hit lymphoma (DHL), an aggressive B-cell lymphoma with a poor prognosis, harbors rearrangements of MYC and BCL2. The standard chemoimmunotherapy comprising R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) yields an unsatisfactory treatment response. Hypomethylating agents increase the susceptibility to malignant lymphoma via the restoration of tumor suppressor genes. Decitabine not only inhibits DNA methylation but also causes mitotic disruption, which leads to antileukemia effects through the covalent binding of DNA methyltransferase 1 to DNA. Previously, we developed an orally bioavailable prodrug of decitabine (OR-2100). Here, we investigated the efficacy and underlying mechanism of OR-2100 as a treatment for DHL. OR-2100 alone or in combination with key antilymphoma drugs, including doxorubicin and vincristine, suppressed the in vitro proliferation of DHL cell lines, particularly those with wild-type TP53. OR-2100 induced downregulation of CDCA8 and BIRC5 (baculoviral IAP [inhibitor of apoptosis] repeat–containing 5), the knockdown of which suppressed the proliferation of DHL cell lines. Both OR-2100 treatment and CDCA8 knockdown led to mitotic perturbation, suggesting that the disruption of mitosis may underlie the antitumor mechanism of OR-2100 given that the efficacy of OR-2100 was dependent on the TP53 status and that CDCA8 and BIRC5 are downstream targets of the E2F1 pathway. These findings suggest that the antitumor activity of OR-2100 may be mediated through inhibition of the E2F1 pathway. The combination of CHOP and OR-2100 reduced the tumor weight significantly in a xenograft mouse model without increased toxicities. The induction of mitotic perturbation might be a key antilymphoma mechanism for OR-2100, and the combination of OR-2100 and CHOP might be a promising treatment strategy for DHL.