Modification of Radiosensitivity Following Chemotherapy Exposure: Potential Implications for Combined-Modality Therapy

Britten, Richard A.

doi:10.1007/978-1-4615-1173-1_14

Cited by 1 publication

(2 citation statements)

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“…However, toxic effects on patients limit the extent to which radiation and chemotherapy can be intensified. Disruption of NHEJ promotes treatment sensitivity (apoptosis) whereas robust repair mediates treatment resistance (cell survival) 45 , 46 and poor clinical outcome. Moreover, since NHEJ occurs without a DNA template, chromosomal aberrations develop.…”

Section: Discussionmentioning

confidence: 99%

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TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer

et al. 2014

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Head and neck cancer (SCCHN) is a common, aggressive, treatment-resistant cancer with a high recurrence rate and mortality, but the mechanism of treatment-resistance remains unclear. Here we describe a mechanism where the AAA-ATPase TRIP13 promotes treatment-resistance. Overexpression of TRIP13 in non-malignant cells results in malignant transformation. High expression of TRIP13 in SCCHN leads to aggressive, treatment-resistant tumors and enhanced repair of DNA damage. Using mass spectrometry, we identify DNA-PKcs complex proteins that mediate non homologous end joining (NHEJ), as TRIP13 binding partners. Using repair-deficient reporter systems, we show that TRIP13 promotes NHEJ, even when homologous recombination is intact. Importantly, overexpression of TRIP13 sensitizes SCCHN to an inhibitor of DNA-PKcs. Thus, this study defines a new mechanism of treatment resistance in SCCHN and underscores the importance of targeting NHEJ to overcome treatment failure in SCCHN and potentially in other cancers that overexpress TRIP13.

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Section: Discussionmentioning

confidence: 99%

“…HR occurs during or immediately after DNA replication, in the S and G2 phases of the cell cycle when a template is available for repair. If the template is badly damaged or unavailable, HR repair cannot occur and the cell dies 45 , 46 .…”

Section: Discussionmentioning

confidence: 99%