Targeting the replication stress response through synthetic lethal strategies in cancer medicine

Area of Science:

• Molecular Biology
• Cancer Therapeutics
• Genomic Integrity

Background:

• The replication stress response (RSR) is a critical pathway involving kinases like ATM, ATR, CHK1/2, and WEE1.
• Cancers rely on RSR to maintain genomic stability under replicative stress.
• Targeting RSR presents a promising strategy for cancer treatment.

Purpose of the Study:

• To review the therapeutic concept of targeting the replication stress response (RSR) in cancer.
• To detail current monotherapy and combination strategies involving RSR-targeting drugs.
• To discuss emerging therapeutic approaches, including targeting Polθ.

Main Methods:

• Review of current literature on RSR pathways and therapeutic interventions.
• Analysis of early-phase clinical trial data for RSR-targeting drug candidates.
• Exploration of RSR's role in overcoming drug resistance, including PARP inhibitor resistance.

Main Results:

• Numerous drug candidates targeting key RSR nodes are in early-phase trials.
• Promising efficacy demonstrated for RSR-targeting agents as monotherapy and in combination therapies.
• RSR targeting shows potential in reversing PARP inhibitor resistance.

Conclusions:

• Targeting the replication stress response is a viable and developing therapeutic strategy in oncology.
• Combination strategies and novel approaches like targeting Polθ warrant further investigation.
• RSR-targeted therapies address significant unmet clinical needs, particularly in drug resistance.