Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway

Abstract

Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness1–4. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood1–6. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a nonapoptotic form of cell death induced by the build-up of toxic lipid peroxides7,8. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes8,9. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death8. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy- resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.

The impact of non-genetic heterogeneity on cancer cell death

“…Analysis of DTPs generated from multiple combinations of cancer cell lines and drugs, for example, showed a common dependence on GPX4 in these subpopulations (Hangauer et al 2017). This is consistent with work discussed above showing a correlation between a mesenchymal gene signature, therapy resistance, and dependence on GPX4 (Viswanathan et al 2017). The combination of GPX4-targeting, ferroptosis-inducing compounds with traditional chemotherapies may therefore enhance anti-tumour efficacy by specifically targeting DTPs in addition to the bulk population of cells in tumour.…”

“…As observed in cancer progression, this transition has been linked to chemoresistance phenotypes; heterogeneity in epithelial versus mesenchymal state as measured by fluorescent lineage markers correlates with resistance to lethal drug treatments in lung and pancreatic cancer (Fischer et al 2015; Zheng et al 2015). Cells in a mesenchymal state that are less sensitive to chemotherapeutics may display other targetable sensitivities, such as a reliance on the lipid peroxide detoxifying enzyme glutathione peroxidase 4 (GPX4); this dependency can be exploited by inducing ferroptosis, an oxidative, non-apoptotic cell death pathway, in mesenchymal cells (Hangauer et al 2017; Viswanathan et al 2017). …”

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

“…The ferroptosis-inducing compound FIN56 depletes CoQ 10 by modulating squalene synthase activity (SQS), which in part drives accumulation of lethal lipid peroxidation (Shimada et al, 2016b). Statin drugs, which inhibit HMG CoA reductase, the rate-limiting enzyme of the mevalonate pathway, sensitize cells to ferroptosis, presumably by depleting CoQ 10 , and possibly by also inhibiting downstream tRNA isopentenylation via TRIT1, which is required for the biosynthesis of GPX4 (Fradejas et al, 2013; Shimada et al, 2016b; Viswanathan et al, 2017). …”

Computational Analyses Connect Small-Molecule Sensitivity to Cellular Features Using Large Panels of Cancer Cell Lines

“…When combined with large-scale genomic and transcriptomic characterization of cancer cell lines, such as those from the Cancer Cell Line Encyclopedia (CCLE) [4] and the Genomics of Drug Sensitivity in Cancer (GDSC) [5–7], small-molecule sensitivity data have been used to identify new candidate cancer dependencies [1–3,8–14]. Their availability has also stimulated development of foundational analysis methods to find novel cancer dependencies in these or similar data, such as those emerging from genetic perturbation experiments in cancer cell lines [15–18].…”