Synthetic lethality and DNA damage response targeting in cancer stem cells: a comprehensive review

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Cancer stem cells (CSCs) drive tumor initiation, metastasis, and resistance to therapy.
• CSCs possess enhanced DNA repair and metabolic plasticity, contributing to treatment failure.
• Understanding CSC biology is crucial for developing effective cancer therapies.

Purpose of the Study:

• To review the intersection of Synthetic Lethality (SL) and DNA Damage Response (DDR) targeting in Cancer Stem Cells (CSCs).
• To explore current and emerging therapeutic strategies for CSC elimination.
• To address challenges and future directions in targeting CSCs for durable cancer control.

Main Methods:

• Literature review of preclinical and clinical studies on SL and DDR targeting in CSCs.
• Synthesis of information on CSC biology, DDR pathways, and therapeutic modalities.
• Analysis of challenges and future prospects in CSC-targeted therapy.

Main Results:

• DDR pathways are dysregulated in cancer, presenting vulnerabilities exploitable by SL strategies.
• DDR inhibitors (PARP, ATR, ATM, DNA-PKcs) and novel SL targets show promise against CSCs.
• Advanced therapies including small molecules, ADCs, CAR cells, and nanoparticles are being developed for CSC elimination.

Conclusions:

• Targeting SL and DDR in CSCs represents a promising approach for overcoming therapeutic resistance.
• Integrated diagnostic platforms with AI, liquid biopsy, and multi-omics are essential for precision oncology.
• Overcoming CSC heterogeneity and tumor microenvironment challenges is key for durable cancer control.