Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition

Abstract

Acquired drug resistance prevents cancer therapies from achieving stable and complete responses.1 Emerging evidence implicates a key role for nonmutational drug resistance mechanisms underlying the survival of residual cancer “persister” cells.2-4 The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse.5 In an earlier report, we found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival.6 Here, we describe the discovery that a similar therapy-resistant cell state underlies the behavior of persister cells derived from a wide range of cancers and drug treatments. Consequently, we show that persister cells acquire a dependency on GPX4. We demonstrate that loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in vivo. These findings support targeting GPX4 as a therapeutic strategy to prevent acquired drug resistance.

Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress

“…It was recently demonstrated that a mesenchymal or persister cell state is highly dependent on GPX4 peroxidase activity for survival, highlighting the potential for co-treatment with GPX4 inhibitors to overcome epithelial-mesenchymal transition (EMT)-related resistance mechanisms (Hangauer et al, 2017; Viswanathan et al, 2017). These results are in line with our findings as low MITF melanoma cells do exhibit mesenchymal-like expression patterns and phenotype (Li et al, 2015).…”

“…Thus, metastasizing cells could be more sensitive to ferroptosis, and treatment with ferroptosis inducing drugs may potentially limit metastasis. Characterization of the in vivo efficacy of ferroptosis inducing compounds is currently limited by lack of compounds with sufficient bioavailability (Viswanathan et al, 2017; Hangauer et al, 2017). However, genetic experiments using GPX4 knockout melanoma cells have demonstrated that increased ferroptosis sensitivity observed in vitro can be recapitulated in vivo either alone or in combination with BRAF inhibition (Viswanathan et al, 2017; Hangauer et al, 2017).…”

The impact of non-genetic heterogeneity on cancer cell death

“…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). …”

“…This combinatorial approach provides a model for the potential therapeutic application of new insights into non-genetic heterogeneity among cancer cells. 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).…”

Regulation of redox balance in cancer and T cells

“…This therapeutic approach is made plausible by the recent advances in targeted antioxidants that scavenge ROS at specific sites such as mitochondrial complex I or III (97,98). Furthermore, identification of cancer cell dependencies on specific antioxidants such as GPX4 encourages the development of molecules that disable such antioxidant proteins to potentiate the distant damaging ROS (66,99). Importantly, the dosage of the anti-and/or pro-oxidants must be regulated to preserve the redox signaling necessary for the healthy cells including anti-tumor T cells.…”