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Metabolic dependency mapping identifies Peroxiredoxin 1 as a driver of resistance to ATM inhibition
Haojian Li1, Takashi Furusawa2, Renzo Cavero2
1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, 37 Convent Drive, Bethesda, MD, 20892, USA; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, 78712, USA.
Abstract:
Metabolic pathways fuel tumor progression and resistance to stress conditions including chemotherapeutic drugs, such as DNA damage response (DDR) inhibitors. Yet, significant gaps persist in how metabolic pathways confer resistance to DDR inhibition in cancer cells. Here, we employed a metabolism-focused CRISPR knockout screen and identified genetic vulnerabilities to DDR inhibitors. We unveiled Peroxiredoxin 1 (PRDX1) as a synthetic lethality partner with Ataxia Telangiectasia Mutated (ATM) kinase. Tumor cells depleted of PRDX1 displayed heightened sensitivity to ATM inhibition in vitro and in mice in a manner dependent on p53 status. Mechanistically, we discovered that the ribosomal protein RPL32 undergoes redox modification on active cysteine residues 91 and 96 upon ATM inhibition, promoting p53 stability and altered cell fitness. Our findings reveal a new pathway whereby RPL32 senses stress and induces p53 activation impairing tumor cell survival.
Insights
Researchers discovered that inhibiting Peroxiredoxin 1 (PRDX1) makes cancer cells more sensitive to DNA damage response (DDR) inhibitors by affecting the stability of the p53 protein.
Area of Science:
- Cancer Biology
- Metabolic Pathways
- Molecular Mechanisms of Cancer
Background:
- Metabolic pathways are crucial for tumor progression and resistance to therapies like DNA damage response (DDR) inhibitors.
- Understanding how cancer cells develop resistance to DDR inhibition is essential for improving treatment strategies.
Purpose of the Study:
- To identify genetic vulnerabilities that confer resistance to DDR inhibitors using a metabolism-focused CRISPR screen.
- To elucidate the molecular mechanisms by which metabolic pathways influence sensitivity to DDR inhibition.
Main Methods:
- A metabolism-focused CRISPR knockout screen was employed to identify genetic vulnerabilities.
- Experiments were conducted in vitro and in mice to assess tumor cell sensitivity to ATM inhibition.
- Mechanistic studies focused on the redox modification of ribosomal protein RPL32.
Main Results:
- Peroxiredoxin 1 (PRDX1) was identified as a synthetic lethality partner with Ataxia Telangiectasia Mutated (ATM) kinase.
- PRDX1-depleted tumor cells showed increased sensitivity to ATM inhibition, dependent on p53 status.
- ATM inhibition led to redox modification of RPL32, promoting p53 stability and impacting cell fitness.
Conclusions:
- PRDX1 is a key factor in conferring resistance to ATM inhibition in cancer cells.
- A novel pathway involving RPL32 sensing stress and inducing p53 activation was uncovered.
- Targeting PRDX1 may represent a therapeutic strategy to enhance the efficacy of DDR inhibitors.
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