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Research
Integrative pharmacogenomic profiling identifies novel cancer drugs and gene networks modulating ferroptosis sensitivity in pan-cancer
Ren-Wang Peng
Inselspital Universitatsspital Bern
Corresponding Author
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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.
Keywords
Ferroptosis, pharmacogenomics, gene signature, ferroptosis-based therapy, precision oncology
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Research
Integrative pharmacogenomic profiling identifies novel cancer drugs and gene networks modulating ferroptosis sensitivity in pan-cancer
Ren-Wang Peng
Inselspital Universitatsspital Bern
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 11 Jun, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cardiothoracic Surgery
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6