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Suppression of Rev3, the catalytic subunit of Polζ, sensitizes drug-resistant lung tumors to chemotherapy
Open accessAbstract
Platinum-based chemotherapeutic drugs are front-line therapies for the treatment of non-small cell lung cancer. However, intrinsic drug resistance limits the clinical efficacy of these agents. Recent evidence suggests that loss of the translesion polymerase, Polζ, can sensitize tumor cell lines to cisplatin, although the relevance of these findings to the treatment of chemoresistant tumors in vivo has remained unclear. Here, we describe a tumor transplantation approach that enables the rapid introduction of defined genetic lesions into a preclinical model of lung adenocarcinoma. Using this approach, we examined the effect of impaired translesion DNA synthesis on cisplatin response in aggressive late-stage lung cancers. In the presence of reduced levels of Rev3, an essential component of Polζ, tumors exhibited pronounced sensitivity to cisplatin, leading to a significant extension in overall survival of treated recipient mice. Additionally, treated Rev3-deficient cells exhibited reduced cisplatin-induced mutation, a process that has been implicated in the induction of secondary malignancies following chemotherapy. Taken together, our data illustrate the potential of Rev3 inhibition as an adjuvant therapy for the treatment of chemoresistant malignancies, and highlight the utility of rapid transplantation methodologies for evaluating mechanisms of chemotherapeutic resistance in preclinical settings.
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“targeting the translesion synthesis polymerase REV3, which restores cisplatin sensitivity to lung tumors [82]”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [82]
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Metadata
- Authors
- Doles, J., Oliver, T. G., Cameron, E. R., Hsu, G., Jacks, T., Walker, G. C., & Hemann, M. T.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- Howard Hughes Medical Institute (US)
- Department of Biology, and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-11-10
- Volume
- 107
- Issue
- 48
- Pages
- 20786-20791
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2996428
- OpenAlex
- W2012012836
- Cited by
- 190
- References
- 40
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 5 · 2023: 8 · 2022: 6 · 2021: 11 · 2020: 26 · 2019: 14 · 2018: 5 · 2017: 16 · 2016: 17 · 2015: 18 · 2014: 16 · 2013: 13 · 2012: 18
- FWCI
- 5.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Howard Hughes Medical Institute
- Massachusetts Institute of Technology (P30-CA14051)
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (P30-CA14051, Grant P30-CA14051)
- National Institutes of Health (5r01ca128803-05, ES002109)
- Ludwig Center at Harvard
- National Cancer Institute (R01-CA128803, CA14051, Koch Institute Support (core) Grant P30-CA14051, Grant P30-CA14051, P30CA014051, P30-CA-14051)
- National Institute of Environmental Health Sciences (ES-015818, P30ES002109, R56ES015818, R01ES015818)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- REV3, pol, translesion synthesis, cisplatin resistance, non-small cell lung cancer, lung adenocarcinoma, chemoresistance, secondary malignancies, tumor transplantation, adjuvant therapy, DNA polymerase
- MeSH terms
- Adenocarcinoma, Animals, Cisplatin, DNA-Directed DNA Polymerase, DNA-Binding Proteins, Drug Screening Assays, Antitumor, Lung Neoplasms, Neoplasm Transplantation, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Drug Resistance, Neoplasm, Catalytic Domain, Cell Line, Tumor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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