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A DNA Repair Inhibitor Isolated from an Ecuadorian Fungal Endophyte Exhibits Synthetic Lethality in PTEN-Deficient
Nneoma Adaku1, Hyun Bong Park2,3, Daniel J Spakowicz4
1Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut 06520, United States.
Abstract:
Disruption of the tumor suppressor PTEN, either at the protein or genomic level, plays an important role in human cancer development. The high frequency of PTEN deficiency reported across several cancer subtypes positions therapeutic approaches that exploit PTEN loss-of-function with the ability to significantly impact the treatment strategies of a large patient population. Here, we report that an endophytic fungus isolated from a medicinal plant produces an inhibitor of DNA double-strand-break repair. Furthermore, the novel alkaloid product, which we have named irrepairzepine (1), demonstrated synthetic lethal targeting in PTEN-deficient glioblastoma cells. Our results uncover a new therapeutic lead for PTEN-deficient cancers and an important molecular tool toward enhancing the efficacy of current cancer treatments.
Insights
A novel compound from fungus, irrepairzepine, targets DNA repair in PTEN-deficient cancers. This discovery offers a new therapeutic strategy for glioblastoma and other cancers with PTEN loss.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- PTEN (phosphatase and tensin homolog) is a critical tumor suppressor.
- Loss of PTEN function is common in various human cancers, including glioblastoma.
- Targeting PTEN-deficient cancers presents a significant therapeutic opportunity.
Purpose of the Study:
- To identify novel inhibitors of DNA double-strand-break repair.
- To evaluate the therapeutic potential of a novel alkaloid, irrepairzepine, in PTEN-deficient cancers.
- To explore irrepairzepine as a molecular tool for cancer treatment.
Main Methods:
- Isolation and characterization of an endophytic fungus from a medicinal plant.
- Identification and structural elucidation of a novel alkaloid, irrepairzepine.
- Assessment of irrepairzepine's effect on DNA double-strand-break repair.
- Evaluation of synthetic lethality in PTEN-deficient glioblastoma cells.
Main Results:
- An endophytic fungus yielded a novel alkaloid inhibitor of DNA double-strand-break repair, named irrepairzepine.
- Irrepairzepine demonstrated synthetic lethal targeting specifically in PTEN-deficient glioblastoma cells.
- The compound shows promise as a new therapeutic lead for PTEN-loss cancers.
Conclusions:
- Irrepairzepine is a novel inhibitor of DNA double-strand-break repair with synthetic lethal activity against PTEN-deficient glioblastoma.
- This finding presents a new therapeutic avenue for PTEN-deficient cancers.
- Irrepairzepine serves as a valuable molecular tool to enhance current cancer therapies.
