Abstract
Alterations in DNA repair pathways are one of the main drivers of cancer insurgence. Nevertheless, cancer cells are more susceptible to DNA damage than normal cells and they rely on specific functional repair pathways to survive. Thanks to advances in genome sequencing, we now have a better idea of which genes are mutated in specific cancers and this prompted the development of inhibitors targeting DNA repair players involved in pathways essential for cancer cells survival. Currently, the pivotal concept is that combining the inhibition of mechanisms on which cancer cells viability depends is the most promising way to treat tumorigenesis. Numerous inhibitors have been developed and for many of them, efficacy has been demonstrated either alone or in combination with chemo or radiotherapy. In this review, we will analyze the principal pathways involved in cell cycle checkpoint and DNA repair focusing on how their alterations could predispose to cancer, then we will explore the inhibitors developed or in development specifically targeting different proteins involved in each pathway, underscoring the rationale behind their usage and how their combination and/or exploitation as adjuvants to classic therapies could help in patients clinical outcome.
Highlights
Cells ability to faithfully repair DNA from insults from endogenous or exogenous sources is essential to maintain viability
It is evident that targeted inhibition of DNA repair and DNA damage checkpoint (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 checkpoint kinase 1 (CHK1), have been demonstrated to be efficiently targeted and several inhibitors are currently being tested
Summary
Cells ability to faithfully repair DNA from insults from endogenous or exogenous sources is essential to maintain viability. Thanks to the advancement of next-generation sequencing technologies, we have a clearer indication of which DNA repair-related genes are mutated in each specific cancer: for example, some breast and ovarian cancers are characterized by mutations in BRCA1/BRCA2, while alterations in MMR genes such as MSH2 or MLH1 are related to colorectal cancer [12] Putting this information together with new synthetic lethality interactions, discovered by novel CRISPR/Cas screening approaches in human cells [13,14], will allow the development of the most effective therapeutic approaches by production of drugs targeting DNA repair enzymes specific for each pathological situation. We will describe how these players can be targeted in cancer therapy and the most encouraging drugs under study, focusing on the rationale behind their usage to improve efficacy of classic therapy or induce specific synthetic lethal interactions
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