Suppression of Rev3, the catalytic subunit of Polζ, sensitizes drug-resistant lung tumors to chemotherapy

Doles, Jason D.; Oliver, Trudy G.; Cameron, Eleanor Ruth; Hsu, Gerald C; Jacks, Tyler; Walker, Graham C.; Hemann, Michael T.

doi:10.1073/pnas.1011409107

Cited by 164 publications

(157 citation statements)

References 42 publications

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“…In a companion article (19), we show that suppression of the translesion polymerase Polζ (Rev3L/Rev7) can sensitize intrinsically chemoresistant lung adenocarcinomas to cisplatin. Using a well-established preclinical model of Burkitt's lymphoma, the Eμ-myc mouse (20), we sought to determine To whom correspondence may be addressed.…”

Section: Resultsmentioning

confidence: 99%

“…1 C and D). Thus, Rev3L suppression can sensitize cells acutely to the cytotoxic effects of cisplatin in vivo in a lymphoma model as well as in a model of an intrinsically chemoresistant model of non-small cell lung cancer (19).…”

Section: Resultsmentioning

confidence: 99%

“…Given the widespread use of CTX and related compounds in the clinic, our results, combined with results showing drug sensitization to lung adenocarcinomas by TLS inhibition (see ref. 19), suggest a rationale for TLS inhibition as an adjuvant therapy for DNA adductforming chemotherapeutics.…”

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confidence: 99%

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Error-prone translesion synthesis mediates acquired chemoresistance

Xie¹,

Doles

Hemann

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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193

207

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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...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Error-prone translesion synthesis mediates acquired chemoresistance

Xie¹,

Doles

Hemann

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

193

207

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“…To further demonstrate the robustness of dCas9-VP64-mediated knockdown, we targeted Rev3l, the catalytic subunit of the translesion polymerase Pol ζ. Whereas the transcriptional repression of Rev3l is not expected to confer a selective growth advantage to cells, lack of Rev3l sensitizes to cisplatin treatment (49,50). Indeed, all sgRNAs targeting Rev3l significantly sensitized dCas9-VP64 ALL cells to cisplatin treatment (SI Appendix, Fig.…”

Section: Mgmt Transcriptional Activation Via Dcas9-vp64 Provokes Cellmentioning

confidence: 99%

Versatile in vivo regulation of tumor phenotypes by dCas9-mediated transcriptional perturbation

Braun

Bruno

Horlbeck

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Targeted transcriptional regulation is a powerful tool to study genetic mediators of cellular behavior. Here, we show that catalytically dead Cas9 (dCas9) targeted to genomic regions upstream or downstream of the transcription start site allows for specific and sustainable geneexpression level alterations in tumor cells in vitro and in syngeneic immune-competent mouse models. We used this approach for a highcoverage pooled gene-activation screen in vivo and discovered previously unidentified modulators of tumor growth and therapeutic response. Moreover, by using dCas9 linked to an activation domain, we can either enhance or suppress target gene expression simply by changing the genetic location of dCas9 binding relative to the transcription start site. We demonstrate that these directed changes in gene-transcription levels occur with minimal off-target effects. Our findings highlight the use of dCas9-mediated transcriptional regulation as a versatile tool to reproducibly interrogate tumor phenotypes in vivo.cancer genetics | cancer models | cancer therapeutic resistance | gene regulation | CRISPR

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“…Multiple translesion DNA synthesis TLS polymerases are implicated in the lesion bypass of DNA intra-strand cross-links, including those generated by DDP. Replicative bypass of DDP adducts requires the cooperative actions of at least three TLS Pol isoforms : Pol , REV1, and Pol [7][8][9][10][11][12][13][14][15][16] . A reduction in Pol or REV1 function renders cells more sensitive to the cytotoxic effects of DDP, and also markedly decreases its mutagenicity in vitro 11 14 .…”

Section: Cis-diamminedichloroplatinummentioning

confidence: 99%

Overexpression of DNA Polymerase ζ Affects Cisplatin Resistance in Ovarian Cancer: An Immunohistochemical Study

Nagashima

Okuda

Nagatsuka

et al. 2013

Showa Univ J Med Sci

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: DNA polymerase Pol participates in translesional bypass replication. Pol has been shown to be an important contributor to cisdiamminedichloroplatinum DDP ; cisplatin -induced genomic instability and the subsequent emergence of resistance in vitro. We immunohistochemically examined the expression of Pol in ovarian cancer tissues to determine whether its expression affects the DDP resistance of human ovarian cancers and also to determine whether Pol expression is a prognostic factor for ovarian cancers. We assessed 76 archival, formalin-fixed, paraffin-embedded tissue samples obtained from patients with epithelial ovarian cancers who underwent their first operation between 2003 and 2011. An ovarian cancer tissue array was also used in this study. Immunohistochemical staining of Pol was performed using an anti-human Pol monoclonal rabbit antibody. The strength of expression of Pol was compared with the DDP resistance and clinical features of the study population. The Pol over-expression in ovarian cancer tissue which compared with epithelial cells in normal ovaries was not affected by the histological types, FIGO stage, or patient age, but Pol was significantly more overexpressed in the DDP-resistant group than in the DDP-sensitive group P 0.043 . Pol over-expression did not significantly affect the survival rate of the ovarian cancer patients ; however, the Pol positive group tended to have a poorer long-term prognosis. In conclusion, ovarian carcinoma patients with Pol over-expression are likely to be resistant to DDP, especially in cases of recurrent disease. These results confirm the previous findings in vitro, wherein Pol modulated the cytotoxicity and mutagenicity of DDP.

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Suppression of Rev3, the catalytic subunit of Polζ, sensitizes drug-resistant lung tumors to chemotherapy

Cited by 164 publications

References 42 publications

Error-prone translesion synthesis mediates acquired chemoresistance

Error-prone translesion synthesis mediates acquired chemoresistance

Versatile in vivo regulation of tumor phenotypes by dCas9-mediated transcriptional perturbation

Overexpression of DNA Polymerase ζ Affects Cisplatin Resistance in Ovarian Cancer: An Immunohistochemical Study

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