Selenite as a dual apoptotic and ferroptotic agent synergizes with EGFR and KRAS inhibitors with epigenetic interference

Background: Selenium, an essential trace element, has previously been investigated as a pro-apoptotic and DNA demethylation agent. It sensitizes the response to chemotherapy in patients who were refractory to cytotoxic agents. Meanwhile, Ferroptosis is a novel approach to Cancer treatment by triggering cell death and reversing drug resistance. The role of selenium in treating Cancer cells harboring druggable oncogenic alterations and its underlying mechanism are largely unknown.

Results: We treated lung adenocarcinoma cell lines-EGFR-mutant H1975 (H1975 ^{EGFR p.L858R and p.T790M}) and KRAS-mutant H358 (H358 ^{KRAS p.G12C}), with sodium selenite to examine its effect on cell Apoptosis, Ferroptosis, and DNA methylation, as well as its interaction with existing targeted therapy, osimertinib, and adagrasib. We observed selenite to be a dual apoptotic and ferroptotic agent on lung Cancer cells, associated with the activation of p38-ATF4-DDIT3 axis in the unfolded protein response. Ferroptosis induction was more remarkable in H1975 than H358. Selenite also altered cellular DNA methylation machinery through downregulating DNMT1 and upregulating TET1, though not as a major mechanism of its activity. Low-dose selenite synergized with osimertinib in EGFR-mutant H1975, and with adagrasib in KRAS-mutant H358, with stronger synergism observed in H1975.

Conclusion: These results suggest that selenite is a potential apoptotic and ferroptotic drug candidate for the treatment of especially EGFR- and potentially KRAS-mutant lung Cancer.

Ferroptosis; Lung adenocarcinoma; Osimertinib; Selenite; Unfolded protein response.