Osimertinib-tolerant lung cancer cells are susceptible to ferroptosis

Abstract

Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR-TKIs), such as osimertinib, show great success in non-small-cell lung cancer patients with EGFR mutated tumors. However, almost all patients develop resistance to EGFR-TKIs owing to secondary EGFR mutations. Although genetic and irreversible resistance mechanisms have been proposed, little is known about non-genetic and reversible resistance mechanisms. From this perspective, a recent study revealed that acute drug exposure generates drug-tolerant persister cells (DTPs) as a form of non-genetic resistance. However, the biological characteristics of DTPs remain unclear. As lipid peroxidation is related to cancer progression and drug resistance, we focused on ferroptosis, namely programmed cell death induced by the accumulation of lipid peroxides, in DTPs. We examined the biological characteristics of ferroptosis in osimertinib-mediated DTPs derived from PC9 lung adenocarcinoma cells. Unlike PC9 cells, established PC9 DTPs were highly sensitive to the ferroptosis inducer RSL3. Accordingly, PC9 DTPs had increased levels of lipid reactive oxygen species and ferrous ion accumulation. Moreover, RSL3-mediated cell death in PC9 DTPs was completely rescued by treatment with the iron chelator deferoxamine. These results suggest that PC9 DTPs showed increased intracellular ferrous ion accumulation and were susceptible to ferroptosis.