Replication Fork Remodeling and Therapy Escape in DNA Damage Response-Deficient Cancers

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Cancers frequently exhibit defects in DNA damage response (DDR) pathways, such as homology-directed repair (HDR), often due to mutations in BRCA1/2.
• This HDR deficiency initially sensitizes tumors to DNA-targeting chemotherapy, including PARP inhibitors.
• However, primary or acquired therapy resistance remains a significant clinical challenge.

Purpose of the Study:

• To explore the mechanisms of chemotherapy resistance in DDR-defective cancers.
• To review recent advances in replication fork (RF) biology and its role in therapy response.
• To discuss the implications of DNA damage tolerance (DDT) pathways and novel tools for personalized cancer therapy.

Main Methods:

• Review of preclinical models to identify chemotherapy resistance mechanisms.
• Analysis of the role of DDR factors in replication fork (RF) stability and therapy sensitivity.
• Examination of DNA damage tolerance (DDT) pathways in cancer genome integrity.

Main Results:

• Restoration of HDR is a common resistance mechanism, but not the sole cause.
• Loss of certain DDR factors can stabilize replication forks (RFs) in BRCA-deficient tumors, leading to acquired drug resistance.
• DDR factors have independent roles in RF biology, influencing therapy sensitivity.

Conclusions:

• Understanding RF biology and DDT pathways is crucial for overcoming chemotherapy resistance in DDR-defective cancers.
• Novel diagnostic and therapeutic strategies can be developed by integrating knowledge of resistance mechanisms.
• Personalized treatment approaches for HDR-deficient tumors can be advanced through a deeper understanding of these processes.