Chromosomal instability not only has a negative effect on survival in triple-negative breast cancer, but also on the well treatable subgroup of luminal A tumors. This suggests a general mechanism independent of subtypes. Increased chromosomal instability (CIN) in triple-negative breast cancer (TNBC) is attributed to a defect in the DNA repair pathway homologous recombination. Homologous recombination (HR) prevents genomic instability by repair and protection of replication. It is unclear whether genetic alterations actually lead to a repair defect or whether superior signaling pathways are of greater importance. Previous studies focused exclusively on the repair function of HR. Here, we show that the regulation of HR by the intra-S-phase damage response at the replication is of overriding importance. A damage response activated by Ataxia telangiectasia and Rad3 related-checkpoint kinase 1 (ATR-CHK1) can prevent replication stress and leads to resistance formation. CHK1 thus has a preferred role over HR in preventing replication stress in TNBC. The signaling cascade ATR-CHK1 can compensate for a double-strand break repair error and lead to resistance of HR-deficient tumors. Established methods for the identification of HR-deficient tumors for Poly(ADP-Ribose)-Polymerase 1 (PARP1) inhibitor therapies should be extended to include analysis of candidates for intra-S phase damage response.

Chromosomal instability (CIN) is an emerging hallmark of cancer and its role in therapeutic responses has been increasingly attracting the attention of the research community. To target the vulnerability of tumors with high CIN, it is important to identify the genes and mechanisms involved in the maintenance of CIN. In our work, we recognize the tumor suppressor gene Phosphatase and Tensin homolog (PTEN) as a potential gene causing CIN in triple-negative breast cancer (TNBC) and show that TNBC with low expression levels of PTEN can be sensitized for the treatment with poly-(ADP-ribose)-polymerase 1 (PARP1) inhibitors, independent of Breast Cancer (BRCA) mutations or a BRCA-like phenotype. In silico analysis of mRNA expression data from 200 TNBC patients revealed low expression of PTEN in tumors with a high CIN70 score. Western blot analysis of TNBC cell lines confirm lower protein expression of PTEN compared to non TNBC cell lines. Further, PTEN-deficient cell lines showed cellular sensitivity towards PARP1 inhibition treatment. DNA fiber assays and examination of chromatin bound protein fractions indicate a protective role of PTEN at stalled replication forks. In this study, we recognize PTEN as a potential CIN-causing gene in TNBC and identify its important role in the replication processes.

Purpose This review article is intended to provide a perspective overview of potential strategies to overcome radiation resistance of tumors through the combined use of immune checkpoint and DNA repair inhibitors. Methods A literature search was conducted in PubMed using the terms (“DNA repair* and DNA damage response* and intracellular immune response* and immune checkpoint inhibition* and radio*”) until January 31, 2023. Articles were manually selected based on their relevance to the topics analyzed. Results Modern radiotherapy offers a wide range of options for tumor treatment. Radiation-resistant subpopulations of the tumor pose a particular challenge for complete cure. This is due to the enhanced activation of molecular defense mechanisms that prevent cell death because of DNA damage. Novel approaches to enhance tumor cure are provided by immune checkpoint inhibitors, but their effectiveness, especially in tumors without increased mutational burden, also remains limited. Combining inhibitors of both immune checkpoints and DNA damage response with radiation may be an attractive option to augment existing therapies and is the subject of the data summarized here. Conclusion The combination of tested inhibitors of DNA damage and immune responses in preclinical models opens additional attractive options for the radiosensitization of tumors and represents a promising application for future therapeutic approaches.