DNA Repair and Therapeutic Strategies in Cancer Stem Cells

Simple Summary A major theory of cancer development is that cancer originates from a specialised type of tumour cell called the cancer stem cell (CSC). Although CSCs comprise a relative subpopulation to the overall heterogeneous tumour mass, they are responsible for cancer establishment, progression, metastasis, and relapse. The eradication of CSCs is therefore vital for long-term patient remission and survival; however, achieving this is challenging as these cells are highly drug resistant compared to the bulk of cancer cells. CSC drug resistance is multifaceted, occurring through multiple extrinsic and intrinsic mechanisms, including an improved ability to repair chemo/radiotherapy-induced DNA lesions. This review summarises the evidence supporting the notion that CSCs display enhanced DNA repair efficiency relative to the bulk tumour population, the possible mechanisms by which this occurs, and discusses strategies of targeting the DNA damage response within CSCs to improve the efficacy of cancer treatment. First-line cancer treatments successfully eradicate the differentiated tumour mass but are comparatively ineffective against cancer stem cells (CSCs), a self-renewing subpopulation thought to be responsible for tumour initiation, metastasis, heterogeneity, and recurrence. CSCs are thus presented as the principal target for elimination during cancer treatment. However, CSCs are challenging to drug target because of numerous intrinsic and extrinsic mechanisms of drug resistance. One such mechanism that remains relatively understudied is the DNA damage response (DDR). CSCs are presumed to possess properties that enable enhanced DNA repair efficiency relative to their highly proliferative bulk progeny, facilitating improved repair of double-strand breaks induced by radiotherapy and most chemotherapeutics. This can occur through multiple mechanisms, including increased expression and splicing fidelity of DNA repair genes, robust activation of cell cycle checkpoints, and elevated homologous recombination-mediated DNA repair. Herein, we summarise the current knowledge concerning improved genome integrity in non-transformed stem cells and CSCs, discuss therapeutic opportunities within the DDR for re-sensitising CSCs to genotoxic stressors, and consider the challenges posed regarding unbiased identification of novel DDR-directed strategies in CSCs. A better understanding of the DDR mediating chemo/radioresistance mechanisms in CSCs could lead to novel therapeutic approaches, thereby enhancing treatment efficacy in cancer patients.