Integrative pharmacogenomic profiling identifies novel cancer drugs and gene networks modulating ferroptosis sensitivity in pan-cancer

Abstract

Background: Ferroptosis is an apoptosis-independent cell death program implicated in various diseases including cancer. Emerging evidence has demonstrated the promise of pharmacological induction of ferroptosis as a novel anti-cancer approach, but the molecular underpinnings of ferroptosis regulation and biomarkers associated with sensitivity to ferroptosis indcuers has been poorly defined. Methods: By implementing integrated pharmacogenomic analysis, we correlated the sensitivity of small-molecule compounds (n=481) against the transcriptomes of solid cancer cell lines (n=659). The potential of a drug compound to modulate ferroptosis was determined by significant (empirical p-value < 0.01) association of drug effectiveness with SLC7A11 expression. To establish generalized gene signatures for ferroptosis sensitivity and resistance, we interrogated drug effects of multiple ferroptosis inducers (n=7) with transcriptomic data of pan-solid cancer cells. Finally, the ferroptosis gene signature was applied to The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) project to identify cancer patients and cells that likely benefit from ferroptosis-based therapeutics. Results: We report, for the first time, the comprehensive identification of cancer drugs with the potential to induce ferroptosis and a generalized gene expression signature predicting ferroptosis response in pan-cancer. Informed by the findings, we reveal an unanticipated role for class I histone deacetylase (HDAC) in regulating ferroptosis and show that targeting HDAC significantly enhances the ferroptosis-promoting effect of Erastin in lung cancer cells. Moreover, our data indicate that small cell lung cancer (SCLC) and isocitrate dehydrogenase ( IDH )-mutant brain tumors are highly primed for ferroptosis, suggesting that relaunching ferroptosis might be an innovative strategy to target these malignancies. Conclusions: Expanding arsenal targeting aberrant ferroptosis and deciphering gene networks dictating ferroptosis sensitivity shed light on ferroptosis regulatory networks and may facilitate biomarker-guided stratification for ferroptosis-based therapy.

First-in-Class Dual Mechanism Ferroptosis-HDAC Inhibitor Hybrids

“…In addition, a similar observation was made on cotreatment of the two types of cells with CETZOLE-1 and SAHA (Figure A). This is in line with literature data, which suggests synergistic effects of HDAC inhibitors and ferroptosis inducers. − The E and Z isomers have different pharmacological behavior with respect to HDAC inhibitory activity, as seen from the activity profiles of both the HDAC controls (bromo-analogs) and the hybrid molecules (Table ). Because of the different activity profiles in the rest of the biological assays, the pure E -analogs will be used and not the mixture.…”

“…The mesenchymal state has been associated with drug resistance and cell migration, and thus, enhanced and selective killing of this subpopulation of cells will lead to reduced drug resistance and tumor metastasis, especially when combined with another cell death mechanism such as apoptosis. Currently, there is intense interest in the combined effects of HDACi and ferroptosis inducers, with respect to cancer treatment and reduced neurotoxicity. − For example, HDACi increase the sensitivity of cells to ferroptosis leading to synergetic killing of cancer cells . In addition, the neuroprotective effects of HDACi can be an added benefit of such drug combinations by attenuating the neurotoxic effects of ferroptotic agents .…”

Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma

“…Normalized level 4 data of reverse phase protein array (RPPA) were downloaded from The Cancer Proteome Atlas (TCPA) database ( ) [ 69 ], which quantified 218 proteins in 61 out of the 87 MPM samples in TCGA. R packages “limma” and “edgeR” were used to normalize the data and identify the differential gene or protein expression, respectively [ 70 ]. Protein-interacting data were downloaded from Agile Protein Interactomes DataServer ( ) [ 71 ], and co-occurring analysis data were downloaded from cBioPortal ( ).…”

Emerging role of ferroptosis in glioblastoma: Therapeutic opportunities and challenges

“…Also, the application of ivosidenib demonstrated a therapeutic effect in IDH1-mutant low-grade glioma and recurrent GBM (Mellinghoff et al, 2020;Tejera et al, 2020). A drug-transcriptome-based analysis reveals a signature of ferroptotic genes enriched in IDH-mutated brain tumors, indicating that IDH-mutated brain tumors may be uniquely vulnerable to FINs (Yang et al, 2020). IDH1 mutation improves erastin-induced lipid ROS accumulation and glutathione depletion, and its metabolite 2-Hydroxyglutarate (2-HG) sensitizes cells to ferroptosis (Wang T. X. et al, 2019).…”