**13. Conclusions**

It is now evident that targeted inhibition of DNA repair and DDC proteins has numerous applications in cancer treatment. The kinases involved in the first phases of DNA damage recognition and cell cycle arrest such as: ATM, ATR, DNA-PK, and CHK1, have been demonstrated to be efficiently targeted and several inhibitors are currently being tested. Importantly, identifying new targets involved in specific pathways and new drugs could allow the development of more personalized therapeutic approaches that may result in reducing the possibility of side-effects and the occurrence of drug resistance.

Another promising application is the combinatorial treatment which takes advantage of simultaneous inhibition of related pathways, leading to an increase of efficacy as compared to the drugs alone. Recently, there is an emerging paradigm that DNA damage, which frequently occurs in cancer cells, leads to the expression of interferon and chemokines activating immune cells in the tumor microenvironment [202]; therefore, immunotherapy combined with drugs inhibiting DNA-repair proteins is now one of the most promising therapies. Numerous ongoing clinical trials are investigating efficacy of these treatments; for instance, PARP inhibitors combined with immune inhibitors (see clinical trials NCT03834519, NCT03851614, NCT03602859, and NCT03308942). Moreover, the efficacy of PARP inhibitors in HR-deficient cancers underlines the importance of the discovery of new synthetically lethal interactions and how these could be exploited in specific cancers, hence promoting development of personalized therapies. The progression in CRISPR/Cas9-based screening has made possible systematic analysis for synthetic lethal drug targets in human cancers leading to the identification of novel genetic cancer targets and eventually the development of effective drugs specific for different pathogenic conditions [203,204].

Finally, DNA damage is repaired by a protein network that is deeply connected; uncovering these connections might generate novel targets to increase efficacy of current in use therapies and overcome resistance development.

**Author Contributions:** All the authors were involved in curation of the manuscript. S.L. and A.G. collect data and wrote the article. A.P. contributed to designing and editing of the manuscript. S.L. was also involved in preparing the figures and tables. T.C. reviewed the manuscript and contributed to organize the conclusions. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by grants assigned to AG by the "Fondazione Pisa" (127/16) and to AP by Associazione Italiana Ricerca sul Cancro (AIRC\_IG19917). SL was supported by a fellowship from Fondazione Umberto Veronesi (Post-Doctoral Fellowship 2020).

**Acknowledgments:** The authors wish to thank all the members of the laboratories for suggestions and comments. Special thanks to Marcella Simili and Michael Minks for critical reading and language editing.

**Conflicts of Interest:** The authors declare no conflict of interest.
