Error-prone translesion synthesis mediates acquired chemoresistance

Abstract

The development of cancer drug resistance is a persistent clinical problem limiting the successful treatment of disseminated malignancies. However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. Error-prone translesional DNA synthesis (TLS) is known to underlie the mutagenic effects of numerous anticancer agents, but little is known as to whether mutation induced by this process is ultimately relevant to tumor drug resistance. Here, we use a tractable mouse model of B-cell lymphoma to interrogate the role of error-prone translesional DNA synthesis in chemotherapyinduced mutation and resistance to front-line chemotherapy. We find that suppression of Rev1, an essential TLS scaffold protein and dCMP transferase, inhibits both cisplatin-and cyclophosphamideinduced mutagenesis. Additionally, by performing repeated cycles of tumor engraftment and treatment, we show that Rev1 plays a critical role in the development of acquired cyclophosphamide resistance. Thus, chemotherapy not only selects for drug-resistant tumor population but also directly promotes the TLS-mediated acquisition of resistance-causing mutations. These data provide an example of an alteration that prevents the acquisition of drug resistance in tumors in vivo. Because TLS also represents a critical mechanism of DNA synthesis in tumor cells following chemotherapy, these data suggest that TLS inhibition may have dual anticancer effects, sensitizing tumors to therapy as well as preventing the emergence of tumor chemoresistance.DNA polymerase | cancer | chemotherapy | relapse T he development of acquired chemoresistance is a persistent clinical problem limiting the successful treatment of disseminated malignancies. Tumors that relapse following initial treatment frequently are refractory to subsequent administration of the initial drug regimen as well as to distinct sets of chemotherapeutics. Although a number of key pathways have been implicated in resistance to conventional chemotherapeutics, including enhanced drug efflux, increased drug metabolism, drug inactivation, enhanced DNA repair, and defects in apoptosis programs (1, 2), the mechanisms by which tumors develop drug resistance-causing mutations remains unclear.At its core, acquired chemoresistance represents the emergence of subpopulations of drug-resistant tumor cells, a phenomenon rooted in the inherent genetic heterogeneity of the tumor itself. This heterogeneity may occur as a consequence of tumor genetic instability, a process known to underlie tumor development in numerous malignancies. Alternatively, cancer therapy itself may promote mutation and subsequent chemoresistance in relapsed tumors. Support for the latter hypothesis comes from several observations. First, conventional chemotherapeutics can be highly mutagenic (3). In fact, considerable work has gone into highlighting the mutagenic properties of platinum-based and other DNA adduct-forming chemotherapeutics as well as the genes that act in the cellular res...

Structural Basis of Rev1-mediated Assembly of a Quaternary Vertebrate Translesion Polymerase Complex Consisting of Rev1, Heterodimeric Polymerase (Pol) ζ, and Pol κ

“…Broadly used chemotherapeutic agents, such as cyclophosphamide, cisplatin, mitomycin C, and psoralens, introduce interstrand cross-links whose repair requires Rev1 in both replication-coupled and replication-independent modes (42,43). Studies of cancer cell lines have suggested that Rev1-mediated translesion synthesis is a major contributor to cancer cell survival and the development of drug resistance in response to cisplatin treatment (44,45), whereas recent mouse studies have shown that knocking down the level of Rev1 delays the development of chemoresistance in drug-susceptible tumors in vivo (46). Additional mouse studies have shown that knocking down Rev3 sensitizes inherently drug-resistant lung adenocarcinomas to cisplatin chemotherapy (47).…”

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

“…During TLS, the first polymerase inserts a nucleotide opposite the lesion and the second polymerase, usually DNA polymerase ζ, extends beyond the lesion. TLS plays an important role in the development of cisplatin resistance and is critical in the repair of ICLs [29] .…”

ATR–Chk1–APC/CCdh1-dependent stabilization of Cdc7–ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

“…It has been postulated that mutation rate is one of the critical determinants of tumor chemoresistance and that chemotherapy itself promotes mutations and subsequent selection of therapyresistant clones. Recently, translesion synthesis polymerases have been implicated in acquired chemoresistance Xie et al 2010). In the light of our results in the damage bypass-promoting role of Cdc7-ASK, we propose that a combination of, e.g., platinum drugs to evoke replication blockade and a small molecule inhibitor of Cdc7 kinase might offer an innovative strategy to help prevent the emergence of drug-resistant recurrent cancer cells.…”