Dual disruption of DNA repair and telomere maintenance for the treatment of head and neck cancer

Shayanne A. Lajud, Danish A. Nagda, Taku Yamashita, Jun Zheng, Nobuaki Tanaka, Waleed M. Abuzeid, Alyssa Civantos, Orysia Bezpalko, Bert W. O'Malley, Daqing Li

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Purpose: Poly(ADP-ribose) polymerases (PARP) and the Mre11, Rad50, and Nbs1 (MRN) complex are key regulators of DNA repair, and have been recently shown to independently regulate telomere length. Sensitivity of cancers to PARPi is largely dependent on the BRCAness of the cells. Unfortunately, the vast majority of cancers are BRCA-proficient. In this study, therefore, we investigated whether a targeted molecular "hit" on the MRN complex, which is upstream of BRCA, can effectively sensitize BRCA-proficient head and neck squamous cell carcinoma (HNSCC) to PARP inhibitor (PARPi).

Experimental Design: Human HNSCC cell lines and a mouse model with HNSCC xenografts were used in this study. In vitro and in vivo studies were conducted to evaluate the effects and underlying mechanisms of dual molecular disruption of PARP and the MRN complex, using a pharmacologic inhibitor and a dominant-negative Nbs1 expression vector, respectively.

Results: Our findings demonstrate that downregulation of the MRN complex disrupts homologous recombination, and, when combined with PARPi, leads to accumulation of lethal DNA double-strand breaks. Moreover, we show that PARPi and MRN complex disruption induces significantly shortening telomere length. Together, our results demonstrate that dual disruption of these pathways causes significant cell death in BRCA-proficient tumor cells both in vitro and in vivo.

Conclusion: Our study, for the first time, elucidates a novel mechanism for MRN complex and PARP inhibition beyond DNA repair, demonstrating the feasibility of a dual disruption approach that extends the utility of PARPi to the treatment of BRCA-proficient cancers.

Original languageEnglish (US)
Pages (from-to)6465-6478
Number of pages14
JournalClinical Cancer Research
Volume20
Issue number24
DOIs
StatePublished - Dec 15 2014
Externally publishedYes

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Telomere
Head and Neck Neoplasms
DNA Repair
Maintenance
Poly(ADP-ribose) Polymerases
Neoplasms
Telomere Shortening
Double-Stranded DNA Breaks
Homologous Recombination
Heterografts
Cell Death
Research Design
Down-Regulation
Poly(ADP-ribose) Polymerase Inhibitors
Cell Line
Carcinoma, squamous cell of head and neck
In Vitro Techniques

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dual disruption of DNA repair and telomere maintenance for the treatment of head and neck cancer. / Lajud, Shayanne A.; Nagda, Danish A.; Yamashita, Taku; Zheng, Jun; Tanaka, Nobuaki; Abuzeid, Waleed M.; Civantos, Alyssa; Bezpalko, Orysia; O'Malley, Bert W.; Li, Daqing.

In: Clinical Cancer Research, Vol. 20, No. 24, 15.12.2014, p. 6465-6478.

Research output: Contribution to journalArticle

Lajud, SA, Nagda, DA, Yamashita, T, Zheng, J, Tanaka, N, Abuzeid, WM, Civantos, A, Bezpalko, O, O'Malley, BW & Li, D 2014, 'Dual disruption of DNA repair and telomere maintenance for the treatment of head and neck cancer', Clinical Cancer Research, vol. 20, no. 24, pp. 6465-6478. https://doi.org/10.1158/1078-0432.CCR-14-0176
Lajud, Shayanne A. ; Nagda, Danish A. ; Yamashita, Taku ; Zheng, Jun ; Tanaka, Nobuaki ; Abuzeid, Waleed M. ; Civantos, Alyssa ; Bezpalko, Orysia ; O'Malley, Bert W. ; Li, Daqing. / Dual disruption of DNA repair and telomere maintenance for the treatment of head and neck cancer. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 24. pp. 6465-6478.
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AU - Nagda, Danish A.

AU - Yamashita, Taku

AU - Zheng, Jun

AU - Tanaka, Nobuaki

AU - Abuzeid, Waleed M.

AU - Civantos, Alyssa

AU - Bezpalko, Orysia

AU - O'Malley, Bert W.

AU - Li, Daqing

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N2 - Purpose: Poly(ADP-ribose) polymerases (PARP) and the Mre11, Rad50, and Nbs1 (MRN) complex are key regulators of DNA repair, and have been recently shown to independently regulate telomere length. Sensitivity of cancers to PARPi is largely dependent on the BRCAness of the cells. Unfortunately, the vast majority of cancers are BRCA-proficient. In this study, therefore, we investigated whether a targeted molecular "hit" on the MRN complex, which is upstream of BRCA, can effectively sensitize BRCA-proficient head and neck squamous cell carcinoma (HNSCC) to PARP inhibitor (PARPi).Experimental Design: Human HNSCC cell lines and a mouse model with HNSCC xenografts were used in this study. In vitro and in vivo studies were conducted to evaluate the effects and underlying mechanisms of dual molecular disruption of PARP and the MRN complex, using a pharmacologic inhibitor and a dominant-negative Nbs1 expression vector, respectively.Results: Our findings demonstrate that downregulation of the MRN complex disrupts homologous recombination, and, when combined with PARPi, leads to accumulation of lethal DNA double-strand breaks. Moreover, we show that PARPi and MRN complex disruption induces significantly shortening telomere length. Together, our results demonstrate that dual disruption of these pathways causes significant cell death in BRCA-proficient tumor cells both in vitro and in vivo.Conclusion: Our study, for the first time, elucidates a novel mechanism for MRN complex and PARP inhibition beyond DNA repair, demonstrating the feasibility of a dual disruption approach that extends the utility of PARPi to the treatment of BRCA-proficient cancers.

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