Epigenetic based synthetic lethal strategies in human cancers

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Loss of DNA damage repair (DDR) pathways occurs in 40-50% of cancers, presenting a vulnerability.
• Synthetic lethality exploits DDR deficiencies in cancer cells by targeting backup repair pathways.
• The inactivation of one gene (e.g., BRCA1/2) combined with inhibition of another (e.g., PARP) leads to cancer cell death.

Purpose of the Study:

• To explore the therapeutic potential of synthetic lethality in cancer.
• To investigate the role of DDR pathways in tumorigenesis and cancer therapy.
• To highlight the significance of both genetic and epigenetic alterations as therapeutic markers.

Main Methods:

• Exploiting synthetic lethality by targeting DDR-deficient cancer cells.
• Utilizing inhibitors for DDR pathways like PARP, ATM, ATR, CHK1/2, and WEE1.
• Investigating epigenetic modifications, such as methylation, in DDR genes.

Main Results:

• PARP inhibition in BRCA1/2-deficient cells is a paradigm for synthetic lethality.
• Numerous DDR inhibitors are in preclinical and clinical development.
• Aberrant epigenetic changes, including methylation of DDR genes (e.g., BRCA1/2, MGMT), offer new therapeutic avenues.

Conclusions:

• Targeting DDR-deficient cancers through synthetic lethality is a viable therapeutic strategy.
• Combination therapies involving DDR inhibitors show significant potential.
• Both genetic and epigenetic alterations in DDR genes can serve as markers for synthetic lethal therapies.