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Article

Pharmacotranscriptomic Analysis Reveals Novel Drugs and Gene Networks Regulating Ferroptosis in Cancer

1
Division of General Thoracic Surgery, Department of BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland
2
Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
*
Authors to whom correspondence should be addressed.
H.Y. and L.Z. contributed equally to this work.
Cancers 2020, 12(11), 3273; https://doi.org/10.3390/cancers12113273
Received: 20 October 2020 / Revised: 30 October 2020 / Accepted: 3 November 2020 / Published: 5 November 2020
(This article belongs to the Special Issue Metabolic Pathways and Redox Homeostasis in Cancer)
Ferroptosis is increasingly recognized as a promising avenue for cancer therapy, while the biomarkers that predict the sensitivity and/or resistance of ferroptosis and the molecular mechanisms that can be therapeutically exploited to modulate ferroptosis are not yet known. Here, we perform an integrated pharmacotranscriptomic analysis to systematically identify compounds and gene networks that regulate ferroptosis. Our results provide mechanistic insights into the deregulation of ferroptosis in cancer and suggest new approaches for ferroptosis-based cancer therapy.
(1) Background: Ferroptosis is an apoptosis-independent cell death program implicated in many diseases including cancer. Emerging evidence suggests ferroptosis as a promising avenue for cancer therapy, but the paucity of mechanistic understanding of ferroptosis regulation and lack of biomarkers for sensitivity to ferroptosis inducers have significantly hampered the utility of ferroptosis-based therapy. (2) Methods: We performed integrated dataset analysis by correlating the sensitivity of small-molecule compounds (n = 481) against the transcriptomes of solid cancer cell lines (n = 659) to identify drug candidates with the potential to induce ferroptosis. Generalizable gene signatures of ferroptosis sensitivity and resistance are defined by interrogating drug effects of ferroptosis inducers (n = 7) with transcriptomic data of pan-solid cancer cells. (3) Results: We report, for the first time, the comprehensive identification of drug compounds that induce ferroptosis and the delineation of generalizable gene signatures of pro- and anti-ferroptosis in pan-cancer. We further reveal that small cell lung cancer (SCLC) and isocitrate dehydrogenase (IDH1/2)-mutant brain tumors show enrichment of pro-ferroptosis gene signature, suggesting a unique vulnerability of SCLC and IDH-mutant tumors to ferroptosis inducers. Finally, we demonstrate that targeting class I histone deacetylase (HDAC) significantly enhances ferroptotic cell death caused by Erastin, an ferroptosis inducer, in lung cancer cells, revealing a previously underappreciated role for HDAC in ferroptosis regulation. (4) Conclusions: Our work reveals novel drug compounds and gene networks that regulate ferroptosis in cancer, which sheds light on the mechanisms of ferroptosis and may facilitate biomarker-guided stratification for ferroptosis-based therapy. View Full-Text
Keywords: ferroptosis; pharmacotranscriptomics; gene signature; ferroptosis-based therapy; HDAC; IDH mutation; small-cell lung cancer; precision oncology ferroptosis; pharmacotranscriptomics; gene signature; ferroptosis-based therapy; HDAC; IDH mutation; small-cell lung cancer; precision oncology
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MDPI and ACS Style

Yang, H.; Zhao, L.; Gao, Y.; Yao, F.; Marti, T.M.; Schmid, R.A.; Peng, R.-W. Pharmacotranscriptomic Analysis Reveals Novel Drugs and Gene Networks Regulating Ferroptosis in Cancer. Cancers 2020, 12, 3273. https://doi.org/10.3390/cancers12113273

AMA Style

Yang H, Zhao L, Gao Y, Yao F, Marti TM, Schmid RA, Peng R-W. Pharmacotranscriptomic Analysis Reveals Novel Drugs and Gene Networks Regulating Ferroptosis in Cancer. Cancers. 2020; 12(11):3273. https://doi.org/10.3390/cancers12113273

Chicago/Turabian Style

Yang, Haitang, Liang Zhao, Yanyun Gao, Feng Yao, Thomas M. Marti, Ralph A. Schmid, and Ren-Wang Peng. 2020. "Pharmacotranscriptomic Analysis Reveals Novel Drugs and Gene Networks Regulating Ferroptosis in Cancer" Cancers 12, no. 11: 3273. https://doi.org/10.3390/cancers12113273

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