Ovarian cancer is one of the most common gynecologic
malignancies in women and has a poor prognosis.
Taxanes are a class of standard first-line chemotherapeutic agents for the treatment of
ovarian cancer. However,
tumor-intrinsic and acquired resistance to
taxanes poses major challenges to improving clinical outcomes. Hence, there is an urgent clinical need to understand the mechanisms of resistance in order to discover potential
biomarkers and therapeutic strategies to increase
taxane sensitivity in
ovarian cancer. Here, we report the identification of an association between the TP53 status and
taxane sensitivity in
ovarian cancer cells through complementary experimental and informatics approaches. We found that TP53 inactivation is associated with
taxane resistance in
ovarian cancer cells, supported by the evidence from (i)
drug sensitivity profiling with bioinformatic analysis of large-scale
cancer therapeutic response and genomic datasets and (ii) gene signature identification based on experimental isogenic cell line models. Further, our studies revealed TP53-dependent gene expression patterns, such as overexpression of ACSM3, as potential predictive
biomarkers of
taxane resistance in
ovarian cancer. The TP53-dependent hyperactivation of the WNT/β-
catenin pathway discovered herein revealed a potential vulnerability to exploit in developing combination therapeutic strategies. Identification of this genotype-phenotype relationship between the TP53 status and
taxane sensitivity sheds light on TP53-directed patient stratification and therapeutic discoveries for
ovarian cancer treatment.