Replication stress: Driver and therapeutic target in genomically instable cancers

Area of Science:

• Genetics
• Cancer Biology
• Molecular Oncology

Background:

• Genomically unstable cancers, such as triple-negative breast cancer and high-grade serous ovarian cancer, exhibit aggressive behavior and complex genomic rearrangements.
• Replication stress, induced by oncogenes or defective replication fork maintenance, is increasingly recognized as a key driver of genomic instability.
• While replication stress promotes cancer development, it also threatens cancer cell viability, suggesting that tumor cells have evolved compensatory mechanisms to survive.

Purpose of the Study:

• To discuss how replication stress drives chromosomal instability in cancer.
• To explore the cell cycle-regulated mechanisms cancer cells use to cope with replication stress.
• To identify potential therapeutic targets within these compensatory mechanisms for treating genomically unstable cancers.

Main Methods:

• Review of current literature on replication stress and genomic instability.
• Analysis of cell cycle regulation and DNA repair pathways in cancer.
• Discussion of therapeutic strategies targeting replication stress response.

Main Results:

• Replication stress is a significant contributor to chromosomal instability and cancer progression.
• Cancer cells possess sophisticated mechanisms, including DNA structure-specific resolvases, cell cycle checkpoint kinases, and mitotic processing of replication intermediates, to manage replication stress.
• Targeting these adaptive mechanisms could selectively eliminate cancer cells with high replication stress.

Conclusions:

• Understanding the interplay between replication stress and cancer cell survival is crucial for developing novel cancer therapies.
• Therapeutic strategies aimed at exploiting the vulnerabilities of cancer cells under replication stress hold promise for treating difficult-to-treat genomically instable cancers.
• Targeting compensatory mechanisms offers a promising avenue for potentiating existing chemotherapeutic approaches.