Inhibition of BRCA2 and Thymidylate Synthase Creates Multidrug Sensitive Tumor Cells via the Induction of Combined “Complementary Lethality”

Rytelewski, Mateusz; Ferguson, Peter J.; Vareki, Saman Maleki; Figueredo, René; Vincent, Mark; Koropatnick, James

doi:10.1038/mtna.2013.7

Cited by 16 publications

(16 citation statements)

References 49 publications

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“…Whereas previous studies showed that HR promotes survival when thymidylate synthase is inhibited, likely a result of disrupted DNA replication (Yang et al, 2008;Rytelewski et al, 2013), the present studies demonstrated that 5-FU incorporated into DNA also activated HR. We also showed that activation of HR repair is, in part, dependent on TDG.…”

Section: Discussioncontrasting

confidence: 42%

Genomically Incorporated 5-Fluorouracil that Escapes UNG-Initiated Base Excision Repair Blocks DNA Replication and Activates Homologous Recombination

Huehls

Huntoon

Joshi

et al. 2016

Molecular Pharmacology

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5-Fluorouracil (5-FU) and its metabolite 5-fluorodeoxyuridine (FdUrd, floxuridine) are chemotherapy agents that are converted to 5-fluorodeoxyuridine monophosphate (FdUMP) and 5-fluorodeoxyuridine triphosphate (FdUTP). FdUMP inhibits thymidylate synthase and causes the accumulation of uracil in the genome, whereas FdUTP is incorporated by DNA polymerases as 5-FU in the genome; however, it remains unclear how either genomically incorporated U or 5-FU contributes to killing. We show that depletion of the uracil DNA glycosylase (UNG) sensitizes tumor cells to FdUrd. Furthermore, we show that UNG depletion does not sensitize cells to the thymidylate synthase inhibitor (raltitrexed), which induces uracil but not 5-FU accumulation, thus indicating that genomically incorporated 5-FU plays a major role in the antineoplastic effects of FdUrd. We also show that 5-FU metabolites do not block the first round of DNA synthesis but instead arrest cells at the G1/S border when cells again attempt replication and activate homologous recombination (HR). This arrest is not due to 5-FU lesions blocking DNA polymerase d but instead depends, in part, on the thymine DNA glycosylase. Consistent with the activation of HR repair, disruption of HR sensitized cells to FdUrd, especially when UNG was disabled. These results show that 5-FU lesions that escape UNG repair activate HR, which promotes cell survival.

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Section: Discussioncontrasting

confidence: 42%

Genomically Incorporated 5-Fluorouracil that Escapes UNG-Initiated Base Excision Repair Blocks DNA Replication and Activates Homologous Recombination

Huehls

Huntoon

Joshi

et al. 2016

Molecular Pharmacology

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“…We have recently reported that concurrent targeting of BRCA2 and thymidylate synthase in A549 and Hela cells with antisense molecules sensitizes these human tumor cells to cisplatin and melphalan in a fashion consistent with complementary lethality [26]. Combined antisense-mediated knockdown of IDO (with stably-incorporated shRNA) and BRCA2 (with transiently-transfected siRNA) increased sensitivity to either olaparib or cisplatin in an additive fashion (Figs.…”

Section: Discussionmentioning

confidence: 97%

“…SiRNA transfection was performed as described previously [26]. Briefly, concentrations of siRNAs targeting human BRCA2 [OnTarget Plus SMARTPool BRCA2 (Dharmacon RNAi Technologies)] that reduced target mRNAs by approximately 70% by 24 h after transfection were determined (10 nM).…”

Section: Methodsmentioning

confidence: 99%

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Indoleamine 2,3-dioxygenase mediates immune-independent human tumor cell resistance to olaparib, gamma radiation, and cisplatin

et al. 2014

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Indoleamine 2,3-dioxygenase-1 (IDO) is an immunosuppressive molecule expressed by most human tumors. IDO levels correlate with poor prognosis in cancer patients and IDO inhibitors are under investigation to enhance endogenous anticancer immunosurveillance. Little is known of immune-independent functions of IDO relevant to cancer therapy. We show, for the first time, that IDO mediates human tumor cell resistance to a PARP inhibitor (olaparib), gamma radiation, cisplatin, and combined treatment with olaparib and radiation, in the absence of immune cells. Antisense-mediated reduction of IDO, alone and (in a synthetic lethal approach) in combination with antisense to the DNA repair protein BRCA2 sensitizes human lung cancer cells to olaparib and cisplatin. Antisense reduction of IDO decreased NAD+ in human tumor cells. NAD+ is essential for PARP activity and these data suggest that IDO mediates treatment resistance independent of immunity and at least partially due to a previously unrecognized role for IDO in DNA repair. Furthermore, IDO levels correlated with accumulation of tumor cells in G1 and depletion of cells in G2/M of the cell cycle, suggesting that IDO effects on cell cycle may also modulate sensitivity to radiation and chemotherapeutic agents. IDO is a potentially valuable therapeutic target in cancer treatment, independent of immune function and in combination with other therapies.

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“…Based on proof‐of‐concept studies (Rytelewski et al., 2013), we developed a second‐generation BRCA2‐targeting antisense oligodeoxynucleotide (ASO). We investigated the potential therapeutic value of the BRCA2 ASO in a setting with concomitant cisplatin treatment by determining the effects on tumor cell proliferation, metabolic response, and metastasis.…”

Section: Introductionmentioning

confidence: 99%

BRCA2 inhibition enhances cisplatin‐mediated alterations in tumor cell proliferation, metabolism, and metastasis

et al. 2014

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Tumor cells have unstable genomes relative to non-tumor cells. Decreased DNA integrity resulting from tumor cell instability is important in generating favorable therapeutic indices, and intact DNA repair mediates resistance to therapy. Targeting DNA repair to promote the action of anti-cancer agents is therefore an attractive therapeutic strategy. BRCA2 is involved in homologous recombination repair. BRCA2 defects increase cancer risk but, paradoxically, cancer patients with BRCA2 mutations have better survival rates. We queried TCGA data and found that BRCA2 alterations led to increased survival in patients with ovarian and endometrial cancer. We developed a BRCA2-targeting second-generation antisense oligonucleotide (ASO), which sensitized human lung, ovarian, and breast cancer cells to cisplatin by as much as 60%. BRCA2 ASO treatment overcame acquired cisplatin resistance in head and neck cancer cells, but induced minimal cisplatin sensitivity in non-tumor cells. BRCA2 ASO plus cisplatin reduced respiration as an early event preceding cell death, concurrent with increased glucose uptake without a difference in glycolysis. BRCA2 ASO and cisplatin decreased metastatic frequency in vivo by 77%. These results implicate BRCA2 as a regulator of metastatic frequency and cellular metabolic response following cisplatin treatment. BRCA2 ASO, in combination with cisplatin, is a potential therapeutic anti-cancer agent.

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Inhibition of BRCA2 and Thymidylate Synthase Creates Multidrug Sensitive Tumor Cells via the Induction of Combined “Complementary Lethality”

Cited by 16 publications

References 49 publications

Genomically Incorporated 5-Fluorouracil that Escapes UNG-Initiated Base Excision Repair Blocks DNA Replication and Activates Homologous Recombination

Genomically Incorporated 5-Fluorouracil that Escapes UNG-Initiated Base Excision Repair Blocks DNA Replication and Activates Homologous Recombination

Indoleamine 2,3-dioxygenase mediates immune-independent human tumor cell resistance to olaparib, gamma radiation, and cisplatin

BRCA2 inhibition enhances cisplatin‐mediated alterations in tumor cell proliferation, metabolism, and metastasis

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