Multi-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells

Cancer cells employ various defense mechanisms against drug-induced cell death. Investigating multi-omics landscapes of cancer cells before and after treatment can reveal resistance mechanisms and inform new therapeutic strategies. We assessed the effects of navitoclax, a BCL2 family inhibitor, on t...

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Bibliographic Details
Published in:Cancers 2020-09, Vol.12 (9), p.2551
Main Authors: Marczyk, Michal, Patwardhan, Gauri A., Zhao, Jun, Qu, Rihao, Li, Xiaotong, Wali, Vikram B., Gupta, Abhishek K., Pillai, Manoj M., Kluger, Yuval, Yan, Qin, Hatzis, Christos, Pusztai, Lajos, Gunasekharan, Vignesh
Format: Article
Language:English
Subjects:
Antineoplastic agents
Breast cancer
Cancer therapies
Cell death
Chromatin
Copy number
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA methylation
Dosage and administration
Drug therapy
Epigenetics
Gene expression
Genomes
Medical prognosis
Patient outcomes
Population
Proteins
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Summary:Cancer cells employ various defense mechanisms against drug-induced cell death. Investigating multi-omics landscapes of cancer cells before and after treatment can reveal resistance mechanisms and inform new therapeutic strategies. We assessed the effects of navitoclax, a BCL2 family inhibitor, on the transcriptome, methylome, chromatin structure, and copy number variations of MDA-MB-231 triple-negative breast cancer (TNBC) cells. Cells were sampled before treatment, at 72 h of exposure, and after 10-day drug-free recovery from treatment. We observed transient alterations in the expression of stress response genes that were accompanied by corresponding changes in chromatin accessibility. Most of these changes returned to baseline after the recovery period. We also detected lasting alterations in methylation states and genome structure that suggest permanent changes in cell population composition. Using single-cell analyses, we identified 2350 genes significantly upregulated in navitoclax-resistant cells and derived an 18-gene navitoclax resistance signature. We assessed the navitoclax-response-predictive function of this signature in four additional TNBC cell lines in vitro and in silico in 619 cell lines treated with 251 different drugs. We observed a drug-specific predictive value in both experiments, suggesting that this signature could help guiding clinical biomarker studies involving navitoclax.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers12092551