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  • American Association for Cancer Research (AACR)  (12)
  • 1
    Online Resource
    Online Resource
    An Immunogenic Model of KRAS-Mutant Lung Cancer Enables Evaluation of Targeted Therapy and Immunotherapy Combinations
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 19 ( 2022-10-04), p. 3435-3448
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 19 ( 2022-10-04), p. 3435-3448
    Abstract: Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumor regression but ultimately fail to elicit cures. As a result, there is an intense interest in how to best combine targeted therapies with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumors with the host immune system are inadequate, in part due to the low tumor mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant KRAS–driven lung cancer with an elevated tumor mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This failed to substantially increase clonal tumor mutational burden and autochthonous tumors remained refractory to immunotherapy. However, establishing clonal cell lines from these tumors enabled the generation of an immunogenic syngeneic transplantation model of KRAS-mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, antitumor immune responses were not directed against neoantigens but instead targeted derepressed endogenous retroviral antigens. The ability of KRASG12C inhibitors to cause regression of KRASG12C -expressing tumors was markedly potentiated by the adaptive immune system, highlighting the importance of using immunocompetent models for evaluating targeted therapies. Overall, this model provides a unique opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer. Significance: This study develops a mouse model of immunogenic KRAS-mutant lung cancer to facilitate the investigation of optimal combinations of targeted therapies with immunotherapies.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-22-0325
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
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    Correction: ER+ Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 4 ( 2019-02-15), p. 1431-1431
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 4 ( 2019-02-15), p. 1431-1431
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-4270
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 3
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    Abstract 4976: Ricolinostat, a selective HDAC6 inhibitor with immunomodulatory properties, has significant antimelanoma activity in vitro and in vivo
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 4976-4976
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 4976-4976
    Abstract: Melanoma is a less common but the most aggressive type of skin cancer and the rates of melanoma have been rising for the last 30 years. Immunotherapy may represent a new treatment paradigm to benefit melanoma patients. Previous studies have identified HDAC6 playing a central role in the regulating melanoma immunogenicity. We have shown that genetic knockdown (KD) of HDAC6 in murine and human melanoma cells resulted in an increased the expression of MHCI and costimulatory molecules as well as melanoma associated antigens. In vivo studies demonstrated that the growth of melanoma cells lacking HDAC6 was significantly delayed as compared to wild-type cells. This growth was further delayed when HDAC6KD melanoma bearing mice were treated with anti-PD-1 antibodies. Recently, we have shown that in vitro treatment of murine melanoma cells with Ricolinostat decreases PD-L1 expression and increases the expression of acetyl tubulin. Surprisingly, in vivo treatment of B16 melanoma bearing animals with increasing concentrations of ricolinostat resulted in a dose-dependent inhibition of melanoma growth (p & lt;0.05). No toxicities were observed at the doses studied; however, the antitumor effect exerted by ricolinostat was not observed when melanoma bearing SCID mice were treated with this compound, indicating that an intact host immune system is required for the observed antitumor activity. In lieu of these previously unknown immunomodulatory properties of ricolinostat, we next assessed the effects of this compound upon T-cells and whether ricolinostat could augment the efficacy of checkpoint blockade in vivo. Murine T-cells were activated with anti-CD3 plus anti-CD28 in the presence or absence of ricolinostat. Then, those T-cells were adoptively transferred into B16 melanoma bearing mice. T-cell subpopulations from the lymph nodes were analyzed ex vivo. We show here that treatment of murine T-cells with ricolinostat resulted in a significant increase in central memory T-cells endowed with a strong anti-melanoma activity in vivo as compared to control group (p & lt;0.05). Finally, the addition of ricolinostat treatment to either anti-CTLA4 or anti-PD1 treatment was associated with an enhanced inhibition of melanoma tumor growth. In summary, our results have identified HDAC6 as a novel target for melanoma immunotherapy and point out ricolinostat as an attractive agent to add to the immuno-oncology armamentarium. Citation Format: Fengdong Cheng, Sodre Andressa, Jie Chen, Alejandro Villagra, David Woods, Jeffrey Weber, Steven Quayle, Jones Simon, Eduardo Sotomayor. Ricolinostat, a selective HDAC6 inhibitor with immunomodulatory properties, has significant antimelanoma activity in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4976. doi:10.1158/1538-7445.AM2017-4976
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-4976
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 4
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    Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Discovery Vol. 5, No. 12 ( 2015-12-01), p. 1282-1295
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 5, No. 12 ( 2015-12-01), p. 1282-1295
    Abstract: The CD19 antigen, expressed on most B-cell acute lymphoblastic leukemias (B-ALL), can be targeted with chimeric antigen receptor–armed T cells (CART-19), but relapses with epitope loss occur in 10% to 20% of pediatric responders. We detected hemizygous deletions spanning the CD19 locus and de novo frameshift and missense mutations in exon 2 of CD19 in some relapse samples. However, we also discovered alternatively spliced CD19 mRNA species, including one lacking exon 2. Pull-down/siRNA experiments identified SRSF3 as a splicing factor involved in exon 2 retention, and its levels were lower in relapsed B-ALL. Using genome editing, we demonstrated that exon 2 skipping bypasses exon 2 mutations in B-ALL cells and allows expression of the N-terminally truncated CD19 variant, which fails to trigger killing by CART-19 but partly rescues defects associated with CD19 loss. Thus, this mechanism of resistance is based on a combination of deleterious mutations and ensuing selection for alternatively spliced RNA isoforms. Significance: CART-19 yield 70% response rates in patients with B-ALL, but also produce escape variants. We discovered that the underlying mechanism is the selection for preexisting alternatively spliced CD19 isoforms with the compromised CART-19 epitope. This mechanism suggests a possibility of targeting alternative CD19 ectodomains, which could improve survival of patients with B-cell neoplasms. Cancer Discov; 5(12); 1282–95. ©2015 AACR. See related commentary by Jackson and Brentjens, p. 1238. This article is highlighted in the In This Issue feature, p. 1225
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-15-1020
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 5
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    Abstract B37: PLX-4107, a selective IKZF2 degrader, reprograms suppressive regulatory T cells and demonstrates anti-tumor activity
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Immunology Research Vol. 10, No. 12_Supplement ( 2022-12-01), p. B37-B37
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 10, No. 12_Supplement ( 2022-12-01), p. B37-B37
    Abstract: Immune checkpoint therapy has demonstrated durable clinical responses in multiple solid tumor types. Reduced clinical response to checkpoint therapy has been linked to the presence of potent immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment that contribute to tumor immune evasion. The transcription factor Helios (IKZF2) is a marker of highly suppressive Tregs and is required to maintain a stable, suppressive Treg cell phenotype in the inflammatory tumor microenvironment. Depletion of IKZF2 in Tregs results in both loss of suppressive activity and conversion of Tregs into effector-like T cells, leading to anti-tumor immunity. Targeted protein degradation using the endogenous Ubiquitin Proteasome System (UPS) has enabled targeting undruggable proteins, such as IKZF2, that have no known small molecule binding pocket. We have designed small molecules that promote a novel interaction between IKZF2 with the E3 ubiquitin ligase substrate receptor, Cereblon, leading to proximity induced protein degradation. PLX-4107 is a novel molecular glue that is a highly selective, potent, and rapid degrader of IKZF2 via the redirection of the E3 substrate receptor, Cereblon. Degradation of IKZF2 by PLX-4107 is blocked in the presence of proteasome and neddylation inhibitors as well as a Cereblon knock-out cell line, confirming that degradation is mediated by the UPS and specifically through the involvement of Cereblon. Proteome-wide analysis demonstrated that PLX-4107 selectively depletes IKZF2 protein levels without degrading other known Cereblon neo-substrates. In vitro, PLX-4107 mediated degradation of IKZF2 resulted in conversion of suppressive Tregs into CD4+ effector-like T cells, coupled with an increased production of the effector cytokines IL2 and IFNg. Oral administration of PLX-4107 to cynomolgus monkeys demonstrated sustained pharmacodynamic response, persistent depletion of IKZF2, and reprogramming of Tregs, consistent with the catalytic mechanism of protein degradation. In vivo, T cell expansion studies showed that administration of PLX-4107 decreased both Treg CD25 expression and proliferation, along with increased activation of CD8+ T effector cells. PLX-4107 was evaluated in in vivo xenograft efficacy studies and demonstrated dose dependent single agent anti-tumor activity that was dependent on the presence of T cells. In addition, co-administration of PLX-4107 and anti-PD-1 antibody Pembrolizumab resulted in tumor growth inhibition and significant combination benefit. PLX-4107 is a novel molecular glue that selectively degrades the undruggable transcription factor, IKZF2. PLX-4107 mediated IKZF2 degradation results in conversion of Tregs to an effector-like T cell phenotype, single agent antitumor activity and the ability to enhance the efficacy of immune checkpoint therapy in vivo. Citation Format: Peggy A Thompson, Pengyu Yang, Linette Yang, Susan Song, Yujun Huang, Xiaoming Li, Alejandro Dearie, Stephen Chien, Mary E Spalding, Gabrielle Blanco, Elizabeth Daniele, Julia Toth, Aleksandar Jamborcic, Gregory Parker, Simon Bailey. PLX-4107, a selective IKZF2 degrader, reprograms suppressive regulatory T cells and demonstrates anti-tumor activity [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B37.
    Type of Medium: Online Resource
    ISSN: 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM22-B37
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
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    Utility of DNA Repair Protein Foci for the Detection of Putative BRCA1 Pathway Defects in Breast Cancer Biopsies
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Research Vol. 7, No. 8 ( 2009-08-01), p. 1304-1309
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 7, No. 8 ( 2009-08-01), p. 1304-1309
    Abstract: The DNA damage response pathway controlled by the breast cancer and Fanconi anemia (FA) genes can be disrupted by genetic or epigenetic mechanisms in breast cancer. Defects in this pathway may render the affected tumors hypersensitive to DNA-damaging agents. The identification of these defects poses a challenge because of the large number of genes involved in the FA/BRCA pathway. Many pathway components form subnuclear repair protein foci upon exposure to ionizing radiation in vitro, but it was unknown whether foci can be detected in live cancer tissues. Thus, the goal of this pilot study was to identify pathway defects by using a novel ex vivo foci biomarker assay on tumor biopsies. Fresh pretreatment biopsy specimens from patients with locally advanced sporadic breast cancer were irradiated or mock-treated in the laboratory (ex vivo). Foci formation of DNA repair proteins BRCA1, FANCD2, and RAD51 was detected by immunofluorescence microscopy. Three out of seven tumors showed intact radiation-induced foci formation, whereas the other four tumors exhibited a defective foci response. Notably, three of the foci-defective tumors were estrogen receptor/progesterone receptor/HER2–negative (triple-negative), a phenotype that has been associated with BRCA1 deficiency. In conclusion, in this pilot study, we report the successful detection of BRCA1, FANCD2, and RAD51 foci in breast cancer biopsies irradiated ex vivo. Our approach represents a potentially powerful biomarker assay for the detection of pre-existing and functionally important defects within the complex FA/BRCA pathway, which may ultimately allow us to tailor cancer treatment to the DNA repair profile of individual tumors. (Mol Cancer Res 2009;7(8):1304–9)
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-09-0149
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2097884-4
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  • 7
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    ER+ Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors
    American Association for Cancer Research (AACR) ; 2018
    In:  Clinical Cancer Research Vol. 24, No. 11 ( 2018-06-01), p. 2517-2529
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 11 ( 2018-06-01), p. 2517-2529
    Abstract: Purpose: This study aimed to identify biomarkers of resistance to endocrine therapy in estrogen receptor–positive (ER+) breast cancers treated with prolonged neoadjuvant letrozole. Experimental Design: We performed targeted DNA and RNA sequencing in 68 ER+ breast cancers from patients treated with preoperative letrozole (median, 7 months). Results: Twenty-four tumors (35%) exhibited a PEPI score ≥4 and/or recurred after a median of 58 months and were considered endocrine resistant. Integration of the 47 most upregulated genes (log FC & gt; 1, FDR & lt; 0.03) in letrozole-resistant tumors with transcription-binding data showed significant overlap with 20 E2F4-regulated genes (P = 2.56E−15). In patients treated with the CDK4/6 inhibitor palbociclib before surgery, treatment significantly decreased expression of 24 of the 47 most upregulated genes in letrozole-resistant tumors, including 18 of the 20 E2F4 target genes. In long-term estrogen-deprived ER+ breast cancer cells, palbociclib also downregulated all 20 E2F4 target genes and P-RB levels, whereas the ER downregulator fulvestrant or paclitaxel only partially suppressed expression of this set of genes and had no effect on P-RB. Finally, an E2F4 activation signature was strongly associated with resistance to aromatase inhibitors in the ACOSOG Z1031B neoadjuvant trial and with an increased risk of relapse in adjuvant-treated ER+ tumors in METABRIC. Conclusions: In tumors resistant to prolonged neoadjuvant letrozole, we identified a gene expression signature of E2F4 target activation. CDK4/6 inhibition suppressed E2F4 target gene expression in estrogen-deprived ER+ breast cancer cells and in patients' ER+ tumors, suggesting a potential benefit of adjuvant CDK4/6 inhibitors in patients with ER+ breast cancer who fail to respond to preoperative estrogen deprivation. Clin Cancer Res; 24(11); 2517–29. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-17-2904
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 8
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    Abstract P6-03-05: AXL-HER2 dimer as mechanism of anti-HER2 acquired resistance in HER2 amplified brest cancer models: A new step towards precision medicine
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. P6-03-05-P6-03-05
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P6-03-05-P6-03-05
    Abstract: Background: Breast cancer (BC) is a heterogeneous disease. HER2+ BC represents between 15-20% of cases. Trastuzumab, a monoclonal antibody, has been successfully improved clinical benefits in both localized and advanced setting. Despite this evidence, many patients experience resistance to therapy. The objective of this study is to analyze AXL receptor as a potential mechanism of resistance and its implication as a prognostic factor. Methods: We used three breast cancer cell lines with acquired resistance to Trastuzumab. Resistant models were generated by treating parental cells (AU565, SKR3, BT474) with constant dose of Trastuzumab (15μg/mL) for 6 months. Cell viability was estimated by MTT assay. Proteins were assessed by Western blot and genes by qRT-PCR. AXL was downregulated by siRNA and a selective tyrosine kinase (TK) AXL inhibitor (TP-0903). Proteins interaction was assessed by immunoprecipitation and Duolink®PLA. The prognostic value of AXL was evaluated in primary tumor in a cohort of HER2+ BC patients treated with Trastuzumab plus chemotherapy from our center (n=33). Results: Acquired resistant cell lines (RCLs) maintained HER2 amplification. RCLs were more proliferative than sensitive parental cell lines. There was an important up-regulation of AXL ( & gt;2.5 fold-change) and epithelial-mesenchymal transition markers (VIM, CDH2, CTNNB1 and FN1) in RCLs (p & lt;0.05). Sensitivity to Trastuzumab was restored by silencing AXL and by using TP-0903 both able to cause a decrease in cell viability and Trastuzumab IC50 (p & lt;0.05). AXL high expression was ligand independent, as GAS6 was not increased. Heterodimerization between AXL and HER2 was observed among our RCLs. In our cohort, AXL high expression was detected in patients who relapsed and it was associated with worse prognosis with a decrease of disease-free survival (p & lt;0.05). The worse prognostic role of AXL was validated in a public data set (p & lt;0.001). Conclusions: Our results suggest: 1) RCLs were more proliferative and showed mesenchymal-like enriched phenotype; 2) AXL-HER2 dimer was identified as a potential mechanism of secondary resistance to Trastuzumab; 3) genetic and pharmacological AXL inhibition restored sensitivity to Trastuzumab in in vitro models; 4) AXL expression was associated with worse prognosis in our HER2+ trastuzumab-treated BC patients and validated in silico. These results showed AXL as a prognostic factor and a potential therapeutic target in HER2+ patients with resistance to Trastuzumab and AXL overexpression. Citation Format: Anna Adam-Artigues, Eduardo Tormo, Raimundo Cervera, Federico Rojo, Alejandro Pérez-Fidalgo, Sandra Zazo, Paula González-Alonso, Cristina Hernándo, María Teresa Martínez, Valentina Gambardella, Jesús Poveda, Soraya Simón, Belén Ortega, Santiago Moragón, Ana Rovira, Joan Albanell, Octavio Burgués, Begoña Bermejo, Pilar Eroles, Ana Lluch, Juan Miguel Cejalvo. AXL-HER2 dimer as mechanism of anti-HER2 acquired resistance in HER2 amplified brest cancer models: A new step towards precision medicine [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-03-05.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-P6-03-05
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 9
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    BRCA1- and BRCA2-Deficient Cells Are Sensitive to Etoposide-Induced DNA Double-Strand Breaks via Topoisomerase II
    American Association for Cancer Research (AACR) ; 2007
    In:  Cancer Research Vol. 67, No. 15 ( 2007-08-01), p. 7078-7081
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 15 ( 2007-08-01), p. 7078-7081
    Abstract: The function of BRCA1 and BRCA2 in DNA repair could affect the sensitivity of cells to cytotoxic agents, and would therefore be an important component of planning therapy for breast and ovarian cancers. Previously, both BRCA1- and BRCA2-deficient tumors were shown to be sensitive to mitomycin C, and the mechanism was presumed to be a defect in the repair of interstrand crosslinks by homologous recombination. Here, we show that both BRCA1 and BRCA2 determine the sensitivity to the cytotoxic drug, etoposide, using genetic complementation of BRCA-deficient cells. Etoposide is known to bind to topoisomerase II and prevent the resolution of the “cleavable complex,” in which one DNA duplex is passed through a second duplex. The specificity of this BRCA-dependent sensitivity was confirmed by the use of aclarubicin, which is a catalytic inhibitor of topoisomerase II and prevents the formation of the cleavable complex. In the presence of aclarubicin, the differential sensitivity of BRCA-proficient and BRCA-deficient cells was lost. Thus, etoposide requires the presence of topoisomerase II to show specific sensitization in the absence of the function of BRCA1 or BRCA2. We conclude that homologous recombination is used in the repair of DNA damage caused by topoisomerase II poisons. Overall, these results suggest that etoposide is a potentially useful drug in the treatment of BRCA-deficient human cancers. [Cancer Res 2007;67(15):7078–81]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-07-0601
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
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  • 10
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    Homologous Recombination Is the Principal Pathway for the Repair of DNA Damage Induced by Tirapazamine in Mammalian Cells
    American Association for Cancer Research (AACR) ; 2008
    In:  Cancer Research Vol. 68, No. 1 ( 2008-01-01), p. 257-265
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 68, No. 1 ( 2008-01-01), p. 257-265
    Abstract: Tirapazamine (3-amino-1,2,4-benzotriazine-1,4-dioxide) is a promising hypoxia-selective cytotoxin that has shown significant activity in advanced clinical trials in combination with radiotherapy and cisplatin. The current study aimed to advance our understanding of tirapazamine-induced lesions and the pathways involved in their repair. We show that homologous recombination plays a critical role in repair of tirapazamine-induced damage because cells defective in homologous recombination proteins XRCC2, XRCC3, Rad51D, BRCA1, or BRCA2 are particularly sensitive to tirapazamine. Consistent with the involvement of homologous recombination repair, we observed extensive sister chromatid exchanges after treatment with tirapazamine. We also show that the nonhomologous end-joining pathway, which predominantly deals with frank double-strand breaks (DSB), is not involved in the repair of tirapazamine-induced DSBs. In addition, we show that tirapazamine preferentially kills mutants both with defects in XPF/ERCC1 (but not in other nucleotide excision repair factors) and with defects in base excision repair. Tirapazamine also induces DNA-protein cross-links, which include stable DNA-topoisomerase I cleavable complexes. We further show that γH2AX, an indicator of DNA DSBs, is induced preferentially in cells in the S phase of the cell cycle. These observations lead us to an overall model of tirapazamine damage in which DNA single-strand breaks, base damage, and DNA-protein cross-links (including topoisomerase I and II cleavable complexes) produce stalling and collapse of replication forks, the resolution of which results in DSB intermediates, requiring homologous recombination and XPF/ERCC1 for their repair. [Cancer Res 2008;68(1):257–65]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-4497
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
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