Combating resistance to DNA damaging agents

DNA damaging agents are widely used in oncology to treat both hematological and solid cancers. Some commonly used modalities include ionizing radiation, platinum drugs (cisplatin, oxaliplatin, and carboplatin), cyclophosphamide, chlorambucil, and temozolomide. By modifying the chemical structure of nucleic acid, these agents induce apoptosis to subsequently eliminate cancer cells from the body. Unfortunately, the efficacy of these agents can be significantly reduced by various factors that drive drug resistance. For example, increases in drug efflux and/or increased drug metabolism can lower the intracellular concentration of an anti-cancer agent thereby reducing its ability to inflict enough DNA damage to induce apoptosis. Another mechanism involves deletions or mutations in proteins associated with several DNA repair pathways that respond to damaged DNA. For example, cancers such as Li-Fraumeni Syndrome and Lynch Syndrome (formerly referred to as hereditary non-polyposis colorectal cancer (HNPCC)) possess mutations in p53, a key regulator in DNA damage response or DNA mismatch repair, respectively [1, 2]. In these cases, the inability of a cancer cell to appropriately respond to DNA damage or repair it allows an oncogenic cell to survive the cellular insults caused by DNA damaging agents. Moreover, cancer cells that survive these insults are more likely to undergo cell division and proliferate rather than die via apoptosis. This occurs as unrepaired DNA lesions are effectively by-passed by two mutually exclusive pathways (Figure (Figure1).1). The first involves homologous recombination which, in most cases, allows for “error-free” by-pass of a lesion. The alternative pathway reflects the ability of DNA polymerases to efficiently insert nucleotides opposite and beyond a DNA lesion. This activity, termed translesion DNA synthesis (TLS), can be highly pro-mutagenic and generate more mutations in a cancer cell [3]. In turn, higher mutation frequencies can create more aggressive cancers and/or lead to tumor recurrence. An unfortunate example of this phenomenon occurs during the treatment of patients diagnosed with glioblastoma multiforme (GBM). Standard treatments for GBM include administration of the DNA alkylating agent, temozolomide. While this drug is initially effective in reducing tumor burden, its efficacy typically diminishes within a year due to the emergence of drug resistance caused by mutagenesis of proteins such as those involved in DNA repair [4]. Indeed, a recent report highlights a role for TLS activity in generating resistance as