DNA repair capacity in multiple pathways predicts chemoresistance in glioblastoma multiforme

Zachary D. Nagel, Gaspar J. Kitange, Shiv K. Gupta, Brian A. Joughin, Isaac A. Chaim, Patrizia Mazzucato, Douglas A. Lauffenburger, Jann N Sarkaria, Leona D. Samson

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Cancer cells can resist the effects of DNA-damaging therapeutic agents via utilization of DNA repair pathways, suggesting that DNA repair capacity (DRC) measurements in cancer cells could be used to identify patients most likely to respond to treatment. However, the limitations of available technologies have so far precluded adoption of this approach in the clinic. We recently developed fluorescence-based multiplexed host cell reactivation (FM-HCR) assays to measure DRC in multiple pathways. Here we apply a mathematical model that uses DRC in multiple pathways to predict cellular resistance to killing by DNA-damaging agents. This model, developed using FM-HCR and drug sensitivity measurements in 24 human lymphoblastoid cell lines, was applied to a panel of 12 patient-derived xenograft (PDX) models of glioblastoma to predict glioblastoma response to treatment with the chemotherapeutic DNA-damaging agent temozolomide. This work showed that, in addition to changes in O6-methylguanine DNA methyltransferase (MGMT) activity, small changes in mismatch repair (MMR), nucleotide excision repair (NER), and homologous recombination (HR) capacity contributed to acquired temozolomide resistance in PDX models and led to reduced relative survival prolongation following temozolomide treatment of orthotopic mouse models in vivo. Our data indicate that measuring the combined status of MMR, HR, NER, and MGMT provided a more robust prediction of temozolomide resistance than assessments of MGMT activity alone.

Original languageEnglish (US)
Pages (from-to)198-206
Number of pages9
JournalCancer Research
Volume77
Issue number1
DOIs
StatePublished - Jan 1 2017

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temozolomide
Glioblastoma
DNA Repair
DNA
Methyltransferases
DNA Mismatch Repair
Homologous Recombination
Heterografts
Fluorescence
Therapeutics
Neoplasms
Theoretical Models
Technology
Cell Line
Survival
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Nagel, Z. D., Kitange, G. J., Gupta, S. K., Joughin, B. A., Chaim, I. A., Mazzucato, P., ... Samson, L. D. (2017). DNA repair capacity in multiple pathways predicts chemoresistance in glioblastoma multiforme. Cancer Research, 77(1), 198-206. https://doi.org/10.1158/0008-5472.CAN-16-1151

DNA repair capacity in multiple pathways predicts chemoresistance in glioblastoma multiforme. / Nagel, Zachary D.; Kitange, Gaspar J.; Gupta, Shiv K.; Joughin, Brian A.; Chaim, Isaac A.; Mazzucato, Patrizia; Lauffenburger, Douglas A.; Sarkaria, Jann N; Samson, Leona D.

In: Cancer Research, Vol. 77, No. 1, 01.01.2017, p. 198-206.

Research output: Contribution to journalArticle

Nagel, ZD, Kitange, GJ, Gupta, SK, Joughin, BA, Chaim, IA, Mazzucato, P, Lauffenburger, DA, Sarkaria, JN & Samson, LD 2017, 'DNA repair capacity in multiple pathways predicts chemoresistance in glioblastoma multiforme', Cancer Research, vol. 77, no. 1, pp. 198-206. https://doi.org/10.1158/0008-5472.CAN-16-1151
Nagel ZD, Kitange GJ, Gupta SK, Joughin BA, Chaim IA, Mazzucato P et al. DNA repair capacity in multiple pathways predicts chemoresistance in glioblastoma multiforme. Cancer Research. 2017 Jan 1;77(1):198-206. https://doi.org/10.1158/0008-5472.CAN-16-1151
Nagel, Zachary D. ; Kitange, Gaspar J. ; Gupta, Shiv K. ; Joughin, Brian A. ; Chaim, Isaac A. ; Mazzucato, Patrizia ; Lauffenburger, Douglas A. ; Sarkaria, Jann N ; Samson, Leona D. / DNA repair capacity in multiple pathways predicts chemoresistance in glioblastoma multiforme. In: Cancer Research. 2017 ; Vol. 77, No. 1. pp. 198-206.
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