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Page 2             van Waardenburg et al. Cancer Drug Resist 2021;4:837-41

               include DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM) and Rad3 related
               kinase (ATR), ATM and checkpoint kinase 1 (CHK1). Furthermore, in the era of precision medicine, the
               precise targeting of these key players provides an opportunity to utilize biomarkers of DNA repair defects to
               select the optimal treatment for each patient in order to maximize the therapeutic index.

               In this Special Issue of Cancer Drug Resistance, we present a collection of basic and translational articles
               discussing the roles that the DNA damage response and repair pathways play in cancer response to
               treatment as well as resistance.

               In the first article, Nickoloff et al.  discuss exploiting the DNA repair pathways to improve radio-
               sensitivity of the tumor and to prevent resistance while also protecting healthy tissue during radiotherapy.
               Currently, more than half of the cancer patients are treated with radiotherapy, which induces among others
               cytotoxic DNA lesions. This review highlights the opportunities to target components of the DNA damage
               response signaling network and the DNA repair pathways that are activated by radiotherapy to increase
               tumor radiosensitivity yet protect normal (healthy) cells. The authors discuss the influence of many
               biological and environmental factors that affect tumor and normal cell response to X-ray, proton, and
               carbon ion radiotherapy. Moreover, they examine the signaling pathways activated by radiotherapy and
               where opportunities are currently taken to sensitize tumor cells to radiotherapy. In continuation of the
               cellular response to radiation, they focus on repairing radiation-induced double-strand DNA breaks by
               non-homologous end-joining and homologous recombination. Furthermore, they discuss future avenues of
               promising drug combinations and potential unacceptable damage to healthy tissue. This review provides an
               excellent overview of the rapid development of compounds that target and sensitize tumor responses to
               tumors to “localized” radiotherapy in combination with “systemic” chemotherapeutics and the potential
               negative effect on healthy tissues.

               The next article, by Gutierrez and O’Connor , reports on DNA direct reversal repair and alkylating agent
               drug resistance. DNA direct reversal repair (DRR) is a unique repair mechanism that does not require a
               DNA synthesis step to “repair” the damage. Humans exhibit two different DRR pathways, the O6-
               methylguanine-DNA methyltransferase (MGMT) and the alkylated DNA repair protein B (AlkB)
               homologs. Many chemotherapeutic regimens contain an alkylating agent to which tumors acquire
               resistance that limits the use of this and other alkylating agents. This review highlights the mechanism of
               action of the DRR pathway enzymes, the development of drug resistance and discusses potential avenues to
               overcome resistance to alkylating agents. As alkylating agents are part of many chemotherapy-based
               treatment combinations, it is interesting to note that the induced damage is independent of the nucleotide,
               yet the level of damage to individual bases does not always correlate with therapeutic outcomes. This
               overview discusses the mechanistic differences between mono- and bi-functional agents, including the
               different alkylating adducts they form. Moreover, they review the simplest form of error-free DNA repair,
               DRR, the enzymes involved, and their catalytic mechanism, the alkylated bases they reverse, and the
               dependency on the mismatch repair pathway for successful treatment outcomes with alkylating agents. This
               review also highlights the mechanism of resistance cells develop to alkylating agents, including enzyme
               upregulation, changes in collaborative DNA repair pathways, and glutamine metabolism. Importantly,
               strategies to exploit these characteristics are discussed to promote successful therapeutic outcomes.

               Saliba et al.  take a mechanistic angle in their overview on the continuing occurrence of treatment-induced
               drug resistance in acute myeloid leukemia (AML). Despite successes and improvements in combination
               treatment of primary and secondary AML, about half the responders still show relapse after 18 months.
               Acquired drug resistance is still a significant roadblock in achieving a prolonged duration of response. They
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