Recent Advances in Therapeutic Application of DNA Damage Response Inhibitors against Cancer

Abstract

: DNA integrity is continuously challenged by intrinsic cellular processes and environmental agents. To overcome this genomic damage, cells have developed multiple signaling pathways collectively named as DNA damage response (DDR) and composed of three components: (i) sensor proteins, which detect DNA damage, (ii) mediators that relay the signal downstream and recruit the repair machinery, and (iii) the repair proteins, which restore the damaged DNA. A flawed DDR and failure to repair the damage lead to the accumulation of genetic lesions and increased genomic instability, which is recognized as a hallmark of cancer. Cancer cells tend to harbor increased mutations in DDR genes and often have fewer DDR pathways than normal cells. This makes cancer cells more dependent on particular DDR pathways and thus become more susceptible to compounds inhibiting those pathways compared to normal cells, which have all the DDR pathways intact. Understanding the roles of different DDR proteins in the DNA damage response and repair pathways and identification of their structures have paved the way for the development of their inhibitors as targeted cancer therapy. In this review, we describe the major participants of various DDR pathways, their significance in carcinogenesis, and focus on the inhibitors developed against several key DDR proteins.

Role of condensates in modulating DNA repair pathways and its implication for chemoresistance

“…Those considerations imply that cancers harboring mutations in DDR enzymes may rely more on the remaining functional DDR pathways to repair DNA lesions than cancers whose DDR enzymes are not mutated. Thus, they may be more susceptible to inhibitory compounds targeting the DDR pathways that remain functional ( 147 ). Therefore, the possibility that DDR enzymes concentrate in condensates participating into DNA repair within the condensates might be exploited to find different therapeutical approaches to specifically target and inhibit the DNA repair ability of cancer cells ( 141 , 142 , 147 ).…”

“…Thus, they may be more susceptible to inhibitory compounds targeting the DDR pathways that remain functional ( 147 ). Therefore, the possibility that DDR enzymes concentrate in condensates participating into DNA repair within the condensates might be exploited to find different therapeutical approaches to specifically target and inhibit the DNA repair ability of cancer cells ( 141 , 142 , 147 ).…”

Thanksgiving to Yeast, the HMGB Proteins History from Yeast to Cancer

“…In 2015, the Nobel Prize in Chemistry was awarded jointly to Tomas Lindahl, Paul Modrich, and Aziz Sancar for mechanistic studies of DNA repair [56]. Cancer cells tend to harbor increased mutations in DNA Damage Response (DRR) genes, which restore the damaged DNA, and often have fewer DDR pathways than normal cells; thus, they become more susceptible to compounds inhibiting those pathways compared to normal cells, a characteristic that is useful in cancer therapy [57].…”

Extracellular Vesicles and Cell Pathways Involved in Cancer Chemoresistance

“…Finally, vesicles can promote tumor cell survival by triggering DNA repair [ 145 ]. Indeed, many anticancer agents target cancer cells, inducing DNA lesions [ 146 , 147 ]. Vesicles that contain in their lumen a long noncoding RNA named SBF2 antisense RNA1 (lncRNA SBF2-AS1) are secreted by glioblastoma cells resistant to temozolomide ( Table 2 ).…”