Acquisition of relative interstrand crosslinker resistance and PARP inhibitor sensitivity in Fanconi anemia head and neck cancers

Anne J. Lombardi, Elizabeth E. Hoskins, Grant D. Foglesong, Kathryn A. Wikenheiser-Brokamp, Lisa Wiesmüller, Helmut Hanenberg, Paul R. Andreassen, Allison J. Jacobs, Susan B. Olson, Winifred W. Keeble, Laura E. Hays, Susanne I. Wells

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Abstract

Purpose: Fanconi anemia is an inherited disorder associated with a constitutional defect in the Fanconi anemia DNA repair machinery that is essential for resolution of DNA interstrand crosslinks. Individuals with Fanconi anemia are predisposed to formation of head and neck squamous cell carcinomas (HNSCC) at a young age. Prognosis is poor, partly due to patient intolerance of chemotherapy and radiation requiring dose reduction, which may lead to early recurrence of disease. Experimental Design: Using HNSCC cell lines derived from the tumors of patients with Fanconi anemia, and murine HNSCC cell lines derived from the tumors of wild-type and Fancc<sup>-/-</sup> mice, we sought to define Fanconi anemia-dependent chemosensitivity and DNA repair characteristics. We utilized DNA repair reporter assays to explore the preference of Fanconi anemia HNSCC cells for non-homologous end joining (NHEJ). Results: Surprisingly, interstrand crosslinker (ICL) sensitivitywas notnecessarily Fanconi anemia-dependent inhuman or murine cell systems. Our results suggest that the increased Ku-dependent NHEJ that is expected in Fanconi anemia cells did not mediate relative ICL resistance. ICL exposure resulted in increased DNA damage sensing and repair by PARP in Fanconi anemia-deficient cells. Moreover, human and murine Fanconi anemia HNSCC cells were sensitive to PARP inhibition, and sensitivity of human cells was attenuated by Fanconi anemia gene complementation. Conclusions: The observed reliance upon PARP-mediated mechanisms reveals a means by which Fanconi anemia HNSCCs can acquire relative resistance to the ICL-based chemotherapy that is a foundation of HNSCC treatment, as well as a potential target for overcoming chemoresistance in the chemosensitive individual.

Original languageEnglish
Pages (from-to)1962-1972
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number8
DOIs
StatePublished - Apr 15 2015

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Fanconi Anemia
Head and Neck Neoplasms
DNA Repair
Tumor Cell Line
Poly(ADP-ribose) Polymerase Inhibitors
Drug Therapy
DNA Damage
Carcinoma, squamous cell of head and neck
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lombardi, A. J., Hoskins, E. E., Foglesong, G. D., Wikenheiser-Brokamp, K. A., Wiesmüller, L., Hanenberg, H., ... Wells, S. I. (2015). Acquisition of relative interstrand crosslinker resistance and PARP inhibitor sensitivity in Fanconi anemia head and neck cancers. Clinical Cancer Research, 21(8), 1962-1972. https://doi.org/10.1158/1078-0432.CCR-14-2616

Acquisition of relative interstrand crosslinker resistance and PARP inhibitor sensitivity in Fanconi anemia head and neck cancers. / Lombardi, Anne J.; Hoskins, Elizabeth E.; Foglesong, Grant D.; Wikenheiser-Brokamp, Kathryn A.; Wiesmüller, Lisa; Hanenberg, Helmut; Andreassen, Paul R.; Jacobs, Allison J.; Olson, Susan B.; Keeble, Winifred W.; Hays, Laura E.; Wells, Susanne I.

In: Clinical Cancer Research, Vol. 21, No. 8, 15.04.2015, p. 1962-1972.

Research output: Contribution to journalArticle

Lombardi, AJ, Hoskins, EE, Foglesong, GD, Wikenheiser-Brokamp, KA, Wiesmüller, L, Hanenberg, H, Andreassen, PR, Jacobs, AJ, Olson, SB, Keeble, WW, Hays, LE & Wells, SI 2015, 'Acquisition of relative interstrand crosslinker resistance and PARP inhibitor sensitivity in Fanconi anemia head and neck cancers', Clinical Cancer Research, vol. 21, no. 8, pp. 1962-1972. https://doi.org/10.1158/1078-0432.CCR-14-2616
Lombardi, Anne J. ; Hoskins, Elizabeth E. ; Foglesong, Grant D. ; Wikenheiser-Brokamp, Kathryn A. ; Wiesmüller, Lisa ; Hanenberg, Helmut ; Andreassen, Paul R. ; Jacobs, Allison J. ; Olson, Susan B. ; Keeble, Winifred W. ; Hays, Laura E. ; Wells, Susanne I. / Acquisition of relative interstrand crosslinker resistance and PARP inhibitor sensitivity in Fanconi anemia head and neck cancers. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 8. pp. 1962-1972.
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abstract = "Purpose: Fanconi anemia is an inherited disorder associated with a constitutional defect in the Fanconi anemia DNA repair machinery that is essential for resolution of DNA interstrand crosslinks. Individuals with Fanconi anemia are predisposed to formation of head and neck squamous cell carcinomas (HNSCC) at a young age. Prognosis is poor, partly due to patient intolerance of chemotherapy and radiation requiring dose reduction, which may lead to early recurrence of disease. Experimental Design: Using HNSCC cell lines derived from the tumors of patients with Fanconi anemia, and murine HNSCC cell lines derived from the tumors of wild-type and Fancc-/- mice, we sought to define Fanconi anemia-dependent chemosensitivity and DNA repair characteristics. We utilized DNA repair reporter assays to explore the preference of Fanconi anemia HNSCC cells for non-homologous end joining (NHEJ). Results: Surprisingly, interstrand crosslinker (ICL) sensitivitywas notnecessarily Fanconi anemia-dependent inhuman or murine cell systems. Our results suggest that the increased Ku-dependent NHEJ that is expected in Fanconi anemia cells did not mediate relative ICL resistance. ICL exposure resulted in increased DNA damage sensing and repair by PARP in Fanconi anemia-deficient cells. Moreover, human and murine Fanconi anemia HNSCC cells were sensitive to PARP inhibition, and sensitivity of human cells was attenuated by Fanconi anemia gene complementation. Conclusions: The observed reliance upon PARP-mediated mechanisms reveals a means by which Fanconi anemia HNSCCs can acquire relative resistance to the ICL-based chemotherapy that is a foundation of HNSCC treatment, as well as a potential target for overcoming chemoresistance in the chemosensitive individual.",
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AU - Hoskins, Elizabeth E.

AU - Foglesong, Grant D.

AU - Wikenheiser-Brokamp, Kathryn A.

AU - Wiesmüller, Lisa

AU - Hanenberg, Helmut

AU - Andreassen, Paul R.

AU - Jacobs, Allison J.

AU - Olson, Susan B.

AU - Keeble, Winifred W.

AU - Hays, Laura E.

AU - Wells, Susanne I.

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N2 - Purpose: Fanconi anemia is an inherited disorder associated with a constitutional defect in the Fanconi anemia DNA repair machinery that is essential for resolution of DNA interstrand crosslinks. Individuals with Fanconi anemia are predisposed to formation of head and neck squamous cell carcinomas (HNSCC) at a young age. Prognosis is poor, partly due to patient intolerance of chemotherapy and radiation requiring dose reduction, which may lead to early recurrence of disease. Experimental Design: Using HNSCC cell lines derived from the tumors of patients with Fanconi anemia, and murine HNSCC cell lines derived from the tumors of wild-type and Fancc-/- mice, we sought to define Fanconi anemia-dependent chemosensitivity and DNA repair characteristics. We utilized DNA repair reporter assays to explore the preference of Fanconi anemia HNSCC cells for non-homologous end joining (NHEJ). Results: Surprisingly, interstrand crosslinker (ICL) sensitivitywas notnecessarily Fanconi anemia-dependent inhuman or murine cell systems. Our results suggest that the increased Ku-dependent NHEJ that is expected in Fanconi anemia cells did not mediate relative ICL resistance. ICL exposure resulted in increased DNA damage sensing and repair by PARP in Fanconi anemia-deficient cells. Moreover, human and murine Fanconi anemia HNSCC cells were sensitive to PARP inhibition, and sensitivity of human cells was attenuated by Fanconi anemia gene complementation. Conclusions: The observed reliance upon PARP-mediated mechanisms reveals a means by which Fanconi anemia HNSCCs can acquire relative resistance to the ICL-based chemotherapy that is a foundation of HNSCC treatment, as well as a potential target for overcoming chemoresistance in the chemosensitive individual.

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