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Published on: January 7, 2019
SOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells
Linda Zhang1,2,3,4,5, Joanne I Hsu1,2,3, Etienne D Braekeleer6
1Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, United States.
Abstract:
The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our results demonstrate a role for SOD1 in the survival of PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers.
Insights
Researchers identified superoxide dismutase-1 (SOD1) as a synthetic-lethal target for cancer cells with mutations in protein phosphatase Mg2+/Mn2+-dependent 1D (PPM1D). Targeting SOD1 may offer a new therapeutic strategy for PPM1D-mutant leukemias and other cancers.
Area of Science:
- Cancer Biology
- Genomics
- Molecular Medicine
Background:
- The DNA damage response is crucial for genome stability and frequently altered in cancer.
- Protein phosphatase Mg2+/Mn2+-dependent 1D (PPM1D) negatively regulates this response and is implicated in various cancers.
- PPM1D alterations present a potential therapeutic vulnerability in oncology.
Purpose of the Study:
- To identify synthetic-lethal interactions with PPM1D.
- To investigate potential therapeutic targets for PPM1D-mutant cancer cells.
- To elucidate the role of redox balance in PPM1D-driven malignancies.
Main Methods:
- CRISPR/Cas9 screening was employed to discover synthetic-lethal dependencies of PPM1D.
- Analysis of the redox landscape and reactive oxygen species (ROS) levels in PPM1D-mutant cells.
- Assessment of superoxide dismutase-1 (SOD1) as a therapeutic target.
Main Results:
- Superoxide dismutase-1 (SOD1) was identified as a synthetic-lethal target for PPM1D-mutant cells.
- PPM1D-mutant cells exhibit a dysregulated redox state with increased ROS and impaired oxidative stress response.
- SOD1 plays a critical role in the survival of PPM1D-mutant leukemia cells.
Conclusions:
- SOD1 is essential for the survival of PPM1D-mutant leukemia cells.
- Targeting SOD1 represents a novel therapeutic strategy for PPM1D-mutant cancers.
- Understanding the redox dysregulation in PPM1D-mutant cancers opens new avenues for treatment.
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