Targeting antioxidant enzymes enhances the therapeutic efficacy of the BCL-XL inhibitor ABT-263 in KRAS-mutant colorectal cancers

Yumi Oh, Hae Rim Jung, Seoyeon Min, Jinjoo Kang, Dongjun Jang, Seungjae Shin, Jiwon Kim, Sang Eun Lee, Chang Ohk Sung, Won Suk Lee, Charles Lee, Eui Man Jeong, Sung Yup Cho

Research output: Contribution to journalArticlepeer-review

Abstract

Cancer chemotherapeutic drugs exert cytotoxic effects by modulating intracellular reactive oxygen species (ROS) levels. However, whether ROS modulates the efficacy of targeted therapeutics remains poorly understood. Previously, we reported that upregulation of the anti-apoptotic protein, BCL-XL, by KRAS activating mutations was a potential target for KRAS-mutant colorectal cancer (CRC) treatment. Here, we demonstrated that the BCL-XL targeting agent, ABT-263, increased intracellular ROS levels and targeting antioxidant pathways augmented the therapeutic efficacy of this BH3 mimetic. ABT-263 induced expression of genes associated with ROS response and increased intracellular ROS levels by enhancing mitochondrial superoxide generation. The superoxide dismutase inhibitor, 2-methoxyestradiol (2-ME), exhibited synergism with ABT-263 in KRAS-mutant CRC cell lines. This synergistic effect was attributed to the inhibition of mTOR-dependent translation of the anti-apoptotic MCL-1 protein via caspase 3-mediated cleavage of AKT and S6K. In addition, combination treatment of ABT-263 and 2-ME demonstrated a synergistic effect in in vivo patient-derived xenografts harboring KRAS mutations. Our data suggest a novel role for ROS in BH3 mimetic-based targeted therapy and provide a novel strategy for treatment of CRC patients with KRAS mutations.

Original languageEnglish
Pages (from-to)123-136
Number of pages14
JournalCancer Letters
Volume497
DOIs
StatePublished - 28 Jan 2021

Keywords

  • 2-Methoxyestradiol
  • ABT-263
  • Antioxidant system
  • Colorectal cancer
  • KRAS mutation

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