Targeting GPX4 induces selective cell death of drug-tolerant persister tumor cells by ferroptosis.

  • Major finding: Targeting GPX4 induces selective cell death of drug-tolerant persister tumor cells by ferroptosis.

  • Concept: GPX4 knockout suppresses tumor relapse in a xenograft model of melanoma treated with BRAF/MEK inhibitors.

  • Impact: GPX4 inhibition may be a therapeutic strategy to prevent the emergence of drug-resistant tumors.

Drug-tolerant “persister” cells can underlie the emergence of drug-resistant tumors, and thus represent an attractive therapeutic target to suppress relapse. Hangauer and colleagues aimed to discover therapeutically targetable vulnerabilities in drug-tolerant persister cells. Treating the HER2-amplified breast cancer cell line BT474 with the HER2 inhibitor lapatinib resulted in a population of quiescent persister cells. Removing lapatinib resulted in regrowth and reacquisition of lapatinib sensitivity, and subsequent lapatinib treatment rederived the persister cell population, suggesting that the persister cell phenotype is a reversible nonmutational mechanism of resistance. RNA sequencing of drug-naïve and persister cells found that persister cells have upregulation of stemness and mesenchymal markers, and downregulation of epithelial markers and antioxidant genes. A compound screen found that the persister cells were sensitive to two inhibitors of the lipid hydroperoxidase GPX4 (RSL3 and ML210), the inhibition of which has been shown to induce ferroptosis. Further, melanoma and breast, lung, and ovarian cancer persister cell models were also sensitive to GPX4 inhibition, whereas the parental cells were far less sensitive. GPX4 inhibitor–mediated cell death was accompanied by accumulation of lipid hydroperoxides, suggesting ferroptotic cell death, and could be rescued by the lipophilic antioxidants ferrostatin-1 or liproxstatin-1, further confirming that GPX4 inhibition induces ferroptosis. Similar results were observed in vivo in a melanoma xenograft model treated with dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor). After treatment with dabrafenib plus trametinib, wild-type tumors relapsed whereas GPX4 knockout tumors did not. Collectively, these findings suggest that targeting GPX4 may induce ferroptosis of persister cells to prevent the acquisition of drug resistance, and these findings may be relevant to multiple tumor types and drug regimens.

Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 2017 Nov 1 [Epub ahead of print].

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