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Preclinical efficacy of the MTH1 inhibitor karonudib in B-cell lymphoma

ABSTRACT: Although chemo-immunotherapy has greatly improved survival of B-cell lymphoma patients, treatment resistant and refractory disease represent a major challenge that call for development of new treatment options. Karonudib (TH1579) is a new drug developed to inhibit MTH1, an enzyme which prevents oxidized dNTPs from being incorporated into DNA. Here, we tested the efficacy of karonudib in vitro and in preclinical models of B-cell lymphoma. Karonudib reduced viability in a wide range of B-cell lymphoma cell lines at concentrations that were well tolerated by activated normal B cells. Induction of mitotic arrest was seen as early as 6 h after karonudib treatment, with induction of apoptosis detected after 12 h. These effects were observed independent of TP53 mutational status. Increased incorporation of 8-oxo-dGTP into DNA, in addition to arrest in prometaphase due to failure in spindle assembly were detected in cells exposed to karonudib, suggesting a dual inhibitory mechanism. Karonudib inhibited tumor growth, led to complete remission in the majority of cases and prolonged survival in two different xenograft mouse models of aggressive B-cell lymphoma, including an ABC DLBCL patient-derived xenograft model. Karonudib was well tolerated in vivo, and no weight loss was observed in treated animals. NUDT1, the gene encoding MTH1, was upregulated in tumor biopsies from ABC and GCB DLBCL and BL patients, as compared to B cells from healthy donors. Together, our preclinical findings provide a rational for further clinical testing of karonudib in aggressive B-cell lymphoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE123449 | GEO | 2018/12/07

REPOSITORIES: GEO

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