Glioblastoma (GBM) patients have an estimated survival of ~15 months with treatment, and the standard of care only modestly enhances patient survival. Identifying
biomarkers representing vulnerabilities may allow for the selection of efficacious
chemotherapy options to address personalized variations in GBM
tumors.
Irinotecan targets
topoisomerase I (TOP1) by forming a ternary DNA-TOP1 cleavage complex (TOP1cc), inducing apoptosis.
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial repair
enzyme that may reduce the effectiveness of
irinotecan. We treated GBM cell lines with increasing concentrations of
irinotecan and compared the IC50 values. We found that the TDP1/TOP1 activity ratio had the strongest correlation (Pearson correlation coefficient R = 0.972, based on the average from three sets of experiments) with IC50 values following
irinotecan treatment. Increasing the TDP1/TOP1 activity ratio by the ectopic expression of wild-type TDP1 increased in
irinotecan IC50, while the expression of the TDP1 catalytic-null mutant did not alter the susceptibility to
irinotecan. The TDP1/TOP1 activity ratio may be a new predictive
indicator for GBM vulnerability to
irinotecan, allowing for the selection of individual patients for
irinotecan treatment based on risk-benefit. Moreover, TDP1 inhibitors may be a novel combination treatment with
irinotecan to improve GBM patient responsiveness to genotoxic
chemotherapies.