Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy

J Clin Invest. 2018 Jan 2;128(1):500-516. doi: 10.1172/JCI92742. Epub 2017 Dec 11.


DNA double-strand breaks (DSBs) are mainly repaired either by homologous recombination (HR) or by nonhomologous end-joining (NHEJ) pathways. Here, we showed that myeloid cell leukemia sequence 1 (Mcl-1) acts as a functional switch in selecting between HR and NHEJ pathways. Mcl-1 was cell cycle-regulated during HR, with its expression peaking in S/G2 phase. While endogenous Mcl-1 depletion reduced HR and enhanced NHEJ, Mcl-1 overexpression resulted in a net increase in HR over NHEJ. Mcl-1 directly interacted with the dimeric Ku protein complex via its Bcl-2 homology 1 and 3 (BH1 and BH3) domains, which are required for Mcl-1 to inhibit Ku-mediated NHEJ. Mcl-1 also promoted DNA resection mediated by the Mre11 complex and HR-dependent DSB repair. Using the Mcl-1 BH1 domain as a docking site, we identified a small molecule, MI-223, that directly bound to BH1 and blocked Mcl-1-stimulated HR DNA repair, leading to sensitization of cancer cells to hydroxyurea- or olaparib-induced DNA replication stress. Combined treatment with MI-223 and hydroxyurea or olaparib exhibited a strong synergy against lung cancer in vivo. This mechanism-driven combination of agents provides a highly attractive therapeutic strategy to improve lung cancer outcomes.

Keywords: Cancer; Cell Biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols* / chemistry
  • Antineoplastic Combined Chemotherapy Protocols* / pharmacology
  • Cellular Senescence* / drug effects
  • Cellular Senescence* / genetics
  • DNA Breaks, Double-Stranded*
  • DNA End-Joining Repair*
  • Drug Delivery Systems*
  • Hydroxyurea / chemistry
  • Hydroxyurea / pharmacology
  • Ku Autoantigen / genetics
  • Ku Autoantigen / metabolism
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Mice
  • Mice, Knockout
  • Molecular Docking Simulation*
  • Myeloid Cell Leukemia Sequence 1 Protein* / antagonists & inhibitors
  • Myeloid Cell Leukemia Sequence 1 Protein* / chemistry
  • Myeloid Cell Leukemia Sequence 1 Protein* / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein* / metabolism
  • Phthalazines / chemistry
  • Phthalazines / pharmacology
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Recombinational DNA Repair*


  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Phthalazines
  • Piperazines
  • Ku Autoantigen
  • olaparib
  • Hydroxyurea