Precision cancer therapy: profiting from tumor specific defects in the DNA damage tolerance system
DNA damage tolerance (DDT) enables replication to continue in the presence of a damaged template and constitutes a key step in DNA interstrand crosslink repair. In this way DDT minimizes replication stress inflicted by a wide range of endogenous and exogenous agents, and provides a critical first li...
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| Vydáno v: | Oncotarget Ročník 9; číslo 27; s. 18832 |
|---|---|
| Hlavní autoři: | , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
10.04.2018
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| ISSN: | 1949-2553, 1949-2553 |
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| Abstract | DNA damage tolerance (DDT) enables replication to continue in the presence of a damaged template and constitutes a key step in DNA interstrand crosslink repair. In this way DDT minimizes replication stress inflicted by a wide range of endogenous and exogenous agents, and provides a critical first line defense against alkylating and platinating chemotherapeutics. Effective DDT strongly depends on damage-induced, site-specific PCNA-ubiquitination at Lysine (K) 164 by the E2/E3 complex (RAD6/18). A survey of The Cancer Genome Atlas (TCGA) revealed a high frequency of tumors presents RAD6/RAD18 bi-allelic inactivating deletions. For instance, 11% of renal cell carcinoma and 5% of pancreatic tumors have inactivating
-deletions and 7% of malignant peripheral nerve sheath tumors lack
. To determine the potential benefit for tumor-specific DDT defects, we followed a genetic approach by establishing unique sets of DDT-proficient
and -defective
lymphoma and breast cancer cell lines. In the absence of exogenous DNA damage,
tumors grew comparably to their
controls
and
. However, DDT-defective lymphomas and breast cancers were compared to their DDT-proficient controls hypersensitive to the chemotherapeutic drug cisplatin (CsPt), both
and
CsPt strongly inhibited tumor growth and the overall survival of tumor bearing mice greatly improved in the DDT-defective condition. These insights open new therapeutic possibilities for precision cancer medicine with DNA damaging chemotherapeutics and optimize Next-Generation-Sequencing (NGS)-based cancer-diagnostics, -therapeutics, and -prognosis. |
|---|---|
| AbstractList | DNA damage tolerance (DDT) enables replication to continue in the presence of a damaged template and constitutes a key step in DNA interstrand crosslink repair. In this way DDT minimizes replication stress inflicted by a wide range of endogenous and exogenous agents, and provides a critical first line defense against alkylating and platinating chemotherapeutics. Effective DDT strongly depends on damage-induced, site-specific PCNA-ubiquitination at Lysine (K) 164 by the E2/E3 complex (RAD6/18). A survey of The Cancer Genome Atlas (TCGA) revealed a high frequency of tumors presents RAD6/RAD18 bi-allelic inactivating deletions. For instance, 11% of renal cell carcinoma and 5% of pancreatic tumors have inactivating
-deletions and 7% of malignant peripheral nerve sheath tumors lack
. To determine the potential benefit for tumor-specific DDT defects, we followed a genetic approach by establishing unique sets of DDT-proficient
and -defective
lymphoma and breast cancer cell lines. In the absence of exogenous DNA damage,
tumors grew comparably to their
controls
and
. However, DDT-defective lymphomas and breast cancers were compared to their DDT-proficient controls hypersensitive to the chemotherapeutic drug cisplatin (CsPt), both
and
CsPt strongly inhibited tumor growth and the overall survival of tumor bearing mice greatly improved in the DDT-defective condition. These insights open new therapeutic possibilities for precision cancer medicine with DNA damaging chemotherapeutics and optimize Next-Generation-Sequencing (NGS)-based cancer-diagnostics, -therapeutics, and -prognosis. DNA damage tolerance (DDT) enables replication to continue in the presence of a damaged template and constitutes a key step in DNA interstrand crosslink repair. In this way DDT minimizes replication stress inflicted by a wide range of endogenous and exogenous agents, and provides a critical first line defense against alkylating and platinating chemotherapeutics. Effective DDT strongly depends on damage-induced, site-specific PCNA-ubiquitination at Lysine (K) 164 by the E2/E3 complex (RAD6/18). A survey of The Cancer Genome Atlas (TCGA) revealed a high frequency of tumors presents RAD6/RAD18 bi-allelic inactivating deletions. For instance, 11% of renal cell carcinoma and 5% of pancreatic tumors have inactivating RAD18-deletions and 7% of malignant peripheral nerve sheath tumors lack RAD6B. To determine the potential benefit for tumor-specific DDT defects, we followed a genetic approach by establishing unique sets of DDT-proficient PcnaK164 and -defective PcnaK164R lymphoma and breast cancer cell lines. In the absence of exogenous DNA damage, PcnaK164R tumors grew comparably to their PcnaK164 controls in vitro and in vivo. However, DDT-defective lymphomas and breast cancers were compared to their DDT-proficient controls hypersensitive to the chemotherapeutic drug cisplatin (CsPt), both in vitro and in vivo. CsPt strongly inhibited tumor growth and the overall survival of tumor bearing mice greatly improved in the DDT-defective condition. These insights open new therapeutic possibilities for precision cancer medicine with DNA damaging chemotherapeutics and optimize Next-Generation-Sequencing (NGS)-based cancer-diagnostics, -therapeutics, and -prognosis.DNA damage tolerance (DDT) enables replication to continue in the presence of a damaged template and constitutes a key step in DNA interstrand crosslink repair. In this way DDT minimizes replication stress inflicted by a wide range of endogenous and exogenous agents, and provides a critical first line defense against alkylating and platinating chemotherapeutics. Effective DDT strongly depends on damage-induced, site-specific PCNA-ubiquitination at Lysine (K) 164 by the E2/E3 complex (RAD6/18). A survey of The Cancer Genome Atlas (TCGA) revealed a high frequency of tumors presents RAD6/RAD18 bi-allelic inactivating deletions. For instance, 11% of renal cell carcinoma and 5% of pancreatic tumors have inactivating RAD18-deletions and 7% of malignant peripheral nerve sheath tumors lack RAD6B. To determine the potential benefit for tumor-specific DDT defects, we followed a genetic approach by establishing unique sets of DDT-proficient PcnaK164 and -defective PcnaK164R lymphoma and breast cancer cell lines. In the absence of exogenous DNA damage, PcnaK164R tumors grew comparably to their PcnaK164 controls in vitro and in vivo. However, DDT-defective lymphomas and breast cancers were compared to their DDT-proficient controls hypersensitive to the chemotherapeutic drug cisplatin (CsPt), both in vitro and in vivo. CsPt strongly inhibited tumor growth and the overall survival of tumor bearing mice greatly improved in the DDT-defective condition. These insights open new therapeutic possibilities for precision cancer medicine with DNA damaging chemotherapeutics and optimize Next-Generation-Sequencing (NGS)-based cancer-diagnostics, -therapeutics, and -prognosis. |
| Author | van der Wiel, Rianne Buoninfante, Olimpia Alessandra van den Berk, Paul C M Jacobs, Heinz Zavrakidis, Ioannis Pilzecker, Bas Aslam, Muhammad Assad van de Ven, Marieke |
| Author_xml | – sequence: 1 givenname: Olimpia Alessandra surname: Buoninfante fullname: Buoninfante, Olimpia Alessandra organization: Division of Tumor Biology and Immunology, Amsterdam, CX 1066, The Netherlands – sequence: 2 givenname: Bas surname: Pilzecker fullname: Pilzecker, Bas organization: Division of Tumor Biology and Immunology, Amsterdam, CX 1066, The Netherlands – sequence: 3 givenname: Muhammad Assad surname: Aslam fullname: Aslam, Muhammad Assad organization: Division of Tumor Biology and Immunology, Amsterdam, CX 1066, The Netherlands – sequence: 4 givenname: Ioannis surname: Zavrakidis fullname: Zavrakidis, Ioannis organization: Division of Psychosocial Research and Epidemiology, Amsterdam, CX 1066, The Netherlands – sequence: 5 givenname: Rianne surname: van der Wiel fullname: van der Wiel, Rianne organization: Division of Tumor Biology and Immunology, Amsterdam, CX 1066, The Netherlands – sequence: 6 givenname: Marieke surname: van de Ven fullname: van de Ven, Marieke organization: Mouse Clinic for Cancer and Aging research (MCCA) Transgenic Facility, The Netherlands Cancer Institute, Amsterdam, CX 1066, The Netherlands – sequence: 7 givenname: Paul C M surname: van den Berk fullname: van den Berk, Paul C M organization: Division of Tumor Biology and Immunology, Amsterdam, CX 1066, The Netherlands – sequence: 8 givenname: Heinz surname: Jacobs fullname: Jacobs, Heinz organization: Division of Tumor Biology and Immunology, Amsterdam, CX 1066, The Netherlands |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29721165$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_1093_nar_gkac545 crossref_primary_10_1093_pnasnexus_pgae242 crossref_primary_10_1080_14728222_2021_1864321 crossref_primary_10_1002_cam4_2203 crossref_primary_10_1007_s11010_025_05291_2 crossref_primary_10_3389_fphar_2021_596535 crossref_primary_10_1080_10409238_2019_1651817 crossref_primary_10_1186_s13059_024_03451_z crossref_primary_10_1371_journal_pone_0210526 crossref_primary_10_1093_nar_gkz531 crossref_primary_10_3390_genes10010010 crossref_primary_10_3389_fonc_2020_00670 crossref_primary_10_3389_fonc_2021_822500 crossref_primary_10_1038_s41598_020_65767_7 |
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| Keywords | precision cancer medicine DNA damage tolerance cancer target cisplatin chemotherapy |
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