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

Yang, Haitang; Zhao, Liang; Gao, Yanyun; Yao, Feng; Marti, Thomas M.; Schmid, Ralph A.; Peng, Ren-Wang (2020). Pharmacotranscriptomic Analysis Reveals Novel Drugs and Gene Networks Regulating Ferroptosis in Cancer. Cancers, 12(11) MDPI AG 10.3390/cancers12113273

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(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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie

UniBE Contributor:

Yang, Haitang; Zhao, Liang; Gao, Yanyun; Marti, Thomas; Schmid, Ralph and Peng, Ren-Wang

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2072-6694

Publisher:

MDPI AG

Language:

English

Submitter:

Thomas Michael Marti

Date Deposited:

05 Jan 2021 10:59

Last Modified:

05 Jan 2021 11:08

Publisher DOI:

10.3390/cancers12113273

PubMed ID:

33167414

Uncontrolled Keywords:

HDAC IDH mutation ferroptosis ferroptosis-based therapy gene signature pharmacotranscriptomics precision oncology small-cell lung cancer

BORIS DOI:

10.7892/boris.150026

URI:

https://boris.unibe.ch/id/eprint/150026

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