A Novel cytarabine analog evokes synthetic lethality by targeting MK2 in p53-deficient cancer cells.

Abstract Most nucleoside anticancer drugs show a primary resistance to p53-deficient or p53-mutated cancer cells and are limited in the clinic to the treatment of hematological malignancies. However, 2′-fluoro-4′-seleno-ara-C (F–Se-Ara-C), a new generation of cytarabine (Ara-C) analogs, exhibited potent antitumor activity against the p53-deficient prostate cancer cell line PC-3. The distinct activity of F–Se-Ara-C was achieved by targeting the synthetic lethal interaction between p53 and mitogen-activated protein kinase-activated protein kinase-2 (MK2). MK2 is a checkpoint effector for DNA damage responses to drive cell cycle arrest and DNA repair in p53-deficient cancer cells. Therefore, targeting MK2 may be an effective therapeutic strategy that induces apoptosis for cancers deficient in p53. F–Se-Ara-C effectively induced anti-prostate cancer activity in vitro and in vivo by inhibition of MK2 activation in p53-deficient prostate cancer cells. Moreover, combining F–Se-Ara-C with cabozantinib, an anticancer drug currently in clinical use, induced synergistic antitumor activity in p53-deficient prostate cancer cells. Taken together, these data show that F–Se-Ara-C may become great anticancer drug candidate with its unique mechanism of action for overcoming the apoptotic resistance of p53-deficient cells by targeting the synthetic lethal interaction.