The TMPRSS2–ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition

Chatterjee, Payel; Choudhary, Gaurav S.; Alswillah, Turkeyah; Xiong, Xiahui; Heston, Warren D.W.; Magi‐Galluzzi, Cristina; Zhang, Junran; Klein, Eric A.

doi:10.1158/1535-7163.mct-14-0865

Cited by 36 publications

(31 citation statements)

References 48 publications

(79 reference statements)

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“…Intriguingly, however, those Ligase IV−/− cells, but not the normal cells, were also p53−/−, due to the inviability of p53+/+ Ligase IV−/− mice, whereas HCT116 and its derivatives are p53+/+. An alternative explanation for the relative lack of sensitization of the Ligase IV−/− HCT116 cells is that these cells, after extended propagation in culture, have acquired upregulated HRR or Alt-NHEJ functions [79], rendering these repair systems less susceptible to PARP inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells

Alotaibi¹,

Sharma²,

Saleh³

et al. 2016

Radiation Research

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Radiotherapy continues to be a primary modality in the treatment of cancer. DNA damage induced by radiation can promote apoptosis as well as both autophagy and senescence, where autophagy and senescence can theoretically function to prolong tumor survival. A primary aim of this work was to investigate the hypothesis that autophagy and/or senescence could be permissive for DNA repair, thereby facilitating tumor cell recovery from radiation-induced growth arrest and/or cell death. In addition, studies were designed to elucidate the involvement of autophagy and senescence in radiation sensitization by PARP inhibitors and the re-emergence of a proliferating tumor cell population. In the context of this work, the relationship between radiation-induced autophagy and senescence was also determined. Studies were performed using DNA repair proficient HCT116 colon carcinoma cells and a repair deficient Ligase IV (−/−) isogenic cell line. Irradiation promoted a parallel induction of autophagy and senescence that was strongly correlated with the extent of persistent H2AX phosphorylation in both cell lines; however inhibition of autophagy failed to suppress senescence, indicating that the two responses were dissociable. Irradiation resulted in a transient arrest in the HCT116 cells while arrest was prolonged in the Ligase IV (−/−) cells; however, both cell lines ultimately recovered proliferative function, which may reflect maintenance of DNA repair capacity. The PARP inhibitors (Olaparib) and (Niraparib) increased the extent of persistent DNA damage induced by radiation as well as the extent of both autophagy and senescence; neither cell line underwent significant apoptosis by radiation alone or in the presence of the PARP inhibitors. Inhibition of autophagy failed to attenuate radiation sensitization, indicating that autophagy was not involved in the action of the PARP inhibitors. As with radiation alone, despite sensitization by PARP inhibition, proliferative recovery was evident within a period of 10–20 days. While inhibition of DNA repair via PARP inhibition may initially sensitize tumor cells to radiation via the promotion of senescence, this strategy does not appear to interfere with proliferative recovery, which could ultimately contribute to disease recurrence.

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Section: Discussionmentioning

confidence: 99%

Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells

Alotaibi¹,

Sharma²,

Saleh³

et al. 2016

Radiation Research

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“…Interestingly, a newly published in vivo study reported that prostate tumour cells carried TMPRSS2-ERG gene fusion, the most common genetic aberration, which is found in approximately 50% of patients with PCa [126,127]. That means an impaired D-NHEJ repair pathway by inhibiting DNA-PKcs and enhancing the PARP inhibitor-mediated radiosensitization [128]. Furthermore, TMPRSS2-ERG expressing tumour cells have elevated levels Rad51 foci and HR activity after IR, indicating an HR compensatory effect for the defective D-NHEJ and the plausible synthetic lethal interaction that may exert between TMPRSS2-ERG expressing tumour cells and PARP inhibitors [128].…”

Section: Discussionmentioning

confidence: 99%

“…That means an impaired D-NHEJ repair pathway by inhibiting DNA-PKcs and enhancing the PARP inhibitor-mediated radiosensitization [128]. Furthermore, TMPRSS2-ERG expressing tumour cells have elevated levels Rad51 foci and HR activity after IR, indicating an HR compensatory effect for the defective D-NHEJ and the plausible synthetic lethal interaction that may exert between TMPRSS2-ERG expressing tumour cells and PARP inhibitors [128]. We hypothesised that PARP-mediated B-NHEJ will gain a more predominant roll in IR-induced DSBs repair following castration and combined treatment of ADT and PARP inhibitor leads to synthetically lethal effect in PCa.…”

Section: Discussionmentioning

confidence: 99%

Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair

et al. 2015

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Chemical castration improves responses to radiotherapy in prostate cancer, but the mechanism is unknown. We hypothesized that this radiosensitization is caused by castration-mediated down-regulation of nonhomologous end joining (NHEJ) repair of DNA double-strand breaks (DSBs). To test this, we enrolled 48 patients with localized prostate cancer in two arms of the study: either radiotherapy first or radiotherapy after neoadjuvant castration treatment. We biopsied patients at diagnosis and before and after castration and radiotherapy treatments to monitor androgen receptor, NHEJ, and DSB repair in verified cancer tissue. We show that patients receiving neoadjuvant castration treatment before radiotherapy had reduced amounts of the NHEJ protein Ku70, impaired radiotherapy-induced NHEJ activity, and higher amounts of unrepaired DSBs, measured by γ-H2AX foci in cancer tissues. This study demonstrates that chemical castration impairs NHEJ activity in prostate cancer tissue, explaining the improved response of patients with prostate cancer to radiotherapy after chemical castration.

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“…While therapeutic targeting of transcription factor oncogenes is intrinsically challenging, on the basis of the interaction of ERG with the DNA repair enzyme PARP1 and DNA protein kinase DNA-PKc, use of PARP inhibitors was shown to inhibit growth of TMPRSS2-ERG -positive prostate cancer xenografts [ 145 ]. Additionally, PARP inhibition was associated with radiosensitization of TMPRSS2 - ERG -positive prostate cancer cells [ 146 , 147 ]. These experimental leads point to possible therapeutic avenues targeting a prevalent gene fusion in a common carcinoma.…”

Section: Gene Fusion Signatures In Personalized Medicine Of Epitheliamentioning

confidence: 99%

Landscape of gene fusions in epithelial cancers: seq and ye shall find

2015

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Enabled by high-throughput sequencing approaches, epithelial cancers across a range of tissue types are seen to harbor gene fusions as integral to their landscape of somatic aberrations. Although many gene fusions are found at high frequency in several rare solid cancers, apart from fusions involving the ETS family of transcription factors which have been seen in approximately 50 % of prostate cancers, several other common solid cancers have been shown to harbor recurrent gene fusions at low frequencies. On the other hand, many gene fusions involving oncogenes, such as those encoding ALK, RAF or FGFR kinase families, have been detected across multiple different epithelial carcinomas. Tumor-specific gene fusions can serve as diagnostic biomarkers or help define molecular subtypes of tumors; for example, gene fusions involving oncogenes such as ERG, ETV1, TFE3, NUT, POU5F1, NFIB, PLAG1, and PAX8 are diagnostically useful. Tumors with fusions involving therapeutically targetable genes such as ALK, RET, BRAF, RAF1, FGFR1–4, and NOTCH1–3 have immediate implications for precision medicine across tissue types. Thus, ongoing cancer genomic and transcriptomic analyses for clinical sequencing need to delineate the landscape of gene fusions. Prioritization of potential oncogenic “drivers” from “passenger” fusions, and functional characterization of potentially actionable gene fusions across diverse tissue types, will help translate these findings into clinical applications. Here, we review recent advances in gene fusion discovery and the prospects for medicine.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0252-1) contains supplementary material, which is available to authorized users.

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The TMPRSS2–ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition

Cited by 36 publications

References 48 publications

Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells

Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells

Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair

Landscape of gene fusions in epithelial cancers: seq and ye shall find

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