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

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.

• Authors: 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
• Journal: Cancer letters (Cancer Lett) Vol. 497 Pg. 123-136 (01 28 2021) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 33068701 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Aniline Compounds
• Antineoplastic Agents
• Antioxidants
• BCL2L1 protein, human
• Biomarkers, Tumor
• KRAS protein, human
• Sulfonamides
• bcl-X Protein
• Thioredoxins
• 2-Methoxyestradiol
• Superoxide Dismutase
• Proto-Oncogene Proteins p21(ras)
• navitoclax

Topics

• 2-Methoxyestradiol (pharmacology)
• Aniline Compounds (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Antioxidants (metabolism)
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Cell Proliferation
• Colorectal Neoplasms (drug therapy, genetics, metabolism, pathology)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mutation
• Proto-Oncogene Proteins p21(ras) (genetics)
• Sulfonamides (pharmacology)
• Superoxide Dismutase (antagonists & inhibitors)
• Thioredoxins (antagonists & inhibitors)
• Transcriptome
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• bcl-X Protein (antagonists & inhibitors)