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Modification of tumour cell metabolism modulates sensitivity to Chk1 inhibitor-induced DNA damage

Andrew J Massey1

  • 1Vernalis Research, Granta Park, Cambridge, CB21 6GB, UK.

Scientific Reports
|January 21, 2017
PubMed

Insights

Checkpoint kinase 1 (Chk1) inhibitors show promise with chemotherapy. Targeting metabolic pathways that support DNA replication can enhance Chk1 inhibitor efficacy in cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Checkpoint kinase 1 (Chk1) inhibitors are investigated as chemotherapy potentiators, particularly with anti-metabolites causing replication stress.
  • Targeting metabolic pathways supplying DNA replication building blocks may enhance DNA damage and Chk1 inhibitor synergy.

Purpose of the Study:

  • To identify metabolic modulators that synergize with Chk1 inhibitors.
  • To investigate the role of cellular metabolism in Chk1 inhibitor-induced DNA damage and sensitivity.

Main Methods:

  • Screening of small molecule metabolism modulators for combinatorial activity with a Chk1 inhibitor.
  • Assessing the impact of metabolic inhibitors (e.g., chloroquine, GSK 2837808A, 2-deoxyglucose, 6-aminonicotinamide) and nutrient withdrawal (glucose, glutamine) on cell cycle, DNA damage, and Chk1 activity.

Main Results:

  • Combinatorial activity was found between a Chk1 inhibitor and chloroquine or the LDHA/LDHB inhibitor GSK 2837808A.
  • Compounds reducing active replication (2-deoxyglucose, 6-aminonicotinamide) increased resistance to Chk1 inhibitor-induced DNA damage.
  • Glucose or glutamine withdrawal induced cell cycle arrest without DNA damage and reduced Chk1 expression/activation.
  • Glutamine starvation conferred resistance to Chk1 inhibition, which was reversible.

Conclusions:

  • Chk1 expression and activation correlate with active DNA replication.
  • Metabolic interventions targeting DNA replication support pathways can modulate Chk1 inhibitor efficacy.
  • Chk1 inhibitors may benefit patients with tumors characterized by a high fraction of replicating cells.

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