Inhibition of mutagenic translesion synthesis: A possible strategy for improving chemotherapy?

Abstract

While DNA damaging chemotherapy can be very effective and even curative in the treatment of certain cancers, intrinsic and acquired drug resistance underlies tumor progression and morbidity in many cancer patients. Intrinsic resistance defines a cell state that is inherently tolerant of drug action. This can include the activation of drug efflux pumps or detoxifying processes that effectively reduce intracellular drug concentration [1]. This can also include a change in the recognition or persistence of DNA damage, mediated by an enhanced DNA repair capability, a blunted DNA damage response, or the ability to proliferate in the presence of DNA damage. Conversely, acquired drug resistance represents a mutational or epigenetic process by which a chemosensitive cell develops 1 or more of the characteristics of an intrinsically resistant cancer cell. Thus, the mechanisms underlying intrinsic and acquired drug resistance are quite distinct. One describes a cell state, and the other describes the capability of reaching that cell state. Yet, these processes are very much coupled in the context of mutagenic translesion synthesis (TLS). As discussed throughout this review, mutagenic TLS polymerases underlie 2 important phenotypes in response to genotoxic chemotherapy. First, they allow for the bypass of modified DNA bases during DNA synthesis, allowing proliferation to continue in the presence of chemotherapy. Second, the low fidelity replication performed by TLS polymerases results in the introduction of inappropriate, nonpairing bases across from modified nucleotides. The bypass function of TLS polymerases is particularly relevant to intrinsic drug resistance. Many tumors, including most pancreatic adenocarcinomas, nonsmall cell lung cancers, and aggressive brain tumors, as well as most metastatic malignancies, fail to significantly regress following chemotherapy [2]. In these tumors, TLS activity contributes to a drug resistant state by promoting the tolerance of DNA damage [3–6]. Conversely, the mutational role of TLS polymerases is central to process of acquired drug resistance. Tumor regression and relapse following chemotherapy is almost always accompanied by the development of drug resistant disease. This may not occur at initial relapse, but upon serial cycles of treatment patients generally succumb to tumors that have acquired intrinsically resistant disease. In fact, for certain cancers the overall prognosis is not dictated by the initial response of the tumor to chemotherapy. Rather, the response of the relapsed tumor to therapy is a significantly better determinant of overall survival. For instance, a high error-prone TLS activity translates into greater tumor adaptation to chemotherapy, while a low error-prone TLS activity leaves tumor in a treatment-naive state. This latter state is amenable to continued long-term treatment of tumors that remain response to treatment with the initial therapy. The dual functions of mutagenic TLS polymerases in intrinsic and acquired chemoresistance make these proteins very attractive potential targets for adjuvant therapy. When combined with front-line genotoxic therapy, these TLS inhibitors would be expected to sensitize tumors to chemotherapy while blocking drug-induced mutation. Consequently, while the generation of such inhibitors is complex, their route to the clinic is more apparent. TLS inhibitors could be applied in combination with the standard of care for many malignancies. By effectively increasing the effects of chemotherapy in target cells, these agents may also allow for a reduction in chemotherapy dose regimens. An added benefit of these agents may be a reduction in the rate of secondary chemotherapy-driven malignancies that occur in patients following successful treatment of the primary disease.