Abstract
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.
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Acknowledgements
This work was supported by the Georgia Research Alliance (Distinguished Investigator award to HF); the NCI Emory Lung Cancer SPORE Career Enhancement Program (P50CA217691 to XM); the Imagine, Innovate and Impact (I3) Funds from the Emory School of Medicine; and through the Georgia CTSA NIH award (UL1-TR002378) and Winship Cancer Institute (NIH 5P30CA138292). CS is a visiting student in the Emory University School of Medicine-Central South University Xiangya School of Medicine student exchange program. XZ is a visiting student from Zhejiang University School of Medicine. AW is a visiting student in the Emory University School of Medicine-Xi’an Jiaotong University Health Science Center student exchange program.
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Conceptualization: CS and HF; In vitro molecular and cellular biology studies: CS, XZ, QN, DC, SD, DF, KQ, XM, and YD; Informatics analysis: AW and AAI; Data analysis: CS, XM, XZ, and HF; Initial manuscript writing: CS, XM, and HF; Funding acquisition, HF; Resources, HF; Supervision, HF. All authors were involved in editing.
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Shu, C., Zheng, X., Wuhafu, A. et al. Acquisition of taxane resistance by p53 inactivation in ovarian cancer cells. Acta Pharmacol Sin 43, 2419–2428 (2022). https://doi.org/10.1038/s41401-021-00847-6
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DOI: https://doi.org/10.1038/s41401-021-00847-6
