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

Jayoung Song, Jinha Yu, Lak Shin Jeong, Sang Kook Lee

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish
Pages (from-to)54-65
Number of pages12
JournalCancer Letters
StatePublished - 28 Jan 2021

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea ( NRF ) Grant funded by the Korean Government (NRF- 2016M3A9B6903499 ).

Publisher Copyright:
© 2020


  • A nucleoside analog F–Se-Ara-C
  • Mitogen-activated protein kinase-activated protein kinase-2 (MK2) inhibition
  • Mitotic catastrophe
  • p53-deficient cancer cells
  • Synthetic lethality


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