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Article

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

1
Yale Cancer Center, Yale School of Medicine, New Haven, CT 06511, USA
2
Department of Data Science and Engineering, Silesian University of Technology, 44-100 Gliwice, Poland
3
Computational Biology & Bioinformatics Program, Yale University, New Haven, CT 06511, USA
4
Department of Pathology, Yale School of Medicine, New Haven, CT 06511, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(9), 2551; https://doi.org/10.3390/cancers12092551
Received: 14 August 2020 / Revised: 3 September 2020 / Accepted: 4 September 2020 / Published: 8 September 2020
Triple negative breast cancer is a disease with limited treatment options and the poorest outcome across all breast cancer subtypes, thus the need for new effective therapies is high. We recently found that navitoclax displays synergistic anti-proliferative and apoptotic activities with other drugs in treatment of triple negative breast cancer cells, but the resistance to treatment is still a limiting factor. Therefore, we investigated the effects of navitoclax treatment on the transcriptome, genome and epigenome in vitro to better understand the process of developing resistance. We discovered and validated a list of multiple, previously unknown markers of drug resistance that can help in patient selection in future clinical trials involving navitoclax.
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. View Full-Text
Keywords: navitoclax; drug resistance; cancer therapy; signature; multi-omics; triple-negative breast cancer navitoclax; drug resistance; cancer therapy; signature; multi-omics; triple-negative breast cancer
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MDPI and ACS Style

Marczyk, M.; Patwardhan, G.A.; Zhao, J.; Qu, R.; Li, X.; Wali, V.B.; Gupta, A.K.; Pillai, M.M.; Kluger, Y.; Yan, Q.; Hatzis, C.; Pusztai, L.; Gunasekharan, V. Multi-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells. Cancers 2020, 12, 2551. https://doi.org/10.3390/cancers12092551

AMA Style

Marczyk M, Patwardhan GA, Zhao J, Qu R, Li X, Wali VB, Gupta AK, Pillai MM, Kluger Y, Yan Q, Hatzis C, Pusztai L, Gunasekharan V. Multi-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells. Cancers. 2020; 12(9):2551. https://doi.org/10.3390/cancers12092551

Chicago/Turabian Style

Marczyk, Michal, Gauri A. Patwardhan, Jun Zhao, Rihao Qu, Xiaotong Li, Vikram B. Wali, Abhishek K. Gupta, Manoj M. Pillai, Yuval Kluger, Qin Yan, Christos Hatzis, Lajos Pusztai, and Vignesh Gunasekharan. 2020. "Multi-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells" Cancers 12, no. 9: 2551. https://doi.org/10.3390/cancers12092551

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