Low-dose selenite synergizes with KRAS inhibitor as a dual apoptotic and ferroptotic agent in lung adenocarcinoma.

Abstract

e21039 Background: Selenium, an essential trace element, has long been investigated as a pro-apoptotic and DNA demethylation agent. It sensitizes the response to chemotherapy in patients refractory to cytostatic agents. Meanwhile, ferroptosis is a novel approach in cancer treatment by triggering cell death and reversing drug resistance. However, the role of selenite in targeted therapy of lung adenocarcinoma (LUAD) and its underlying mechanism to demethylation and ferroptosis are largely unknown. Methods: EGFR- and KRAS-mutant LUAD cells (H1975 EGFR p.L858R and p.T790M and H358 KRAS p.G12C) were treated with selenite for 72 hours to examine its effect on DNA methylation, apoptosis and ferroptosis by western blot, C-11 BODIPY staining, methylation-specific PCR and transcriptome sequencing validated by qPCR and western blot. Cell proliferation and apoptosis of both cells treated with selenite and osimertinib in H1975 or adagrasib in H358 were assessed by MTS assay and western blot. Results: We confirmed selenite to be a dual apoptotic and ferroptotic agent in LUAD, associated with the activation of the p38-ATF4-CHOP axis in the unfolded protein response. This pathway linked ferroptosis with apoptosis by the upregulation of BH3-only proteins. Selenite also altered the DNA methylation machinery by downregulating DNMT1 and upregulation of TET1. We further found that low-dose selenite synergized with adagrasib in KRAS-mutant H358 but only yielded additive interaction at a high dose. Conclusions: Selenite is a dual apoptotic and ferroptotic agent with dose-dependent, oncogenic driver-dependent therapeutic effects in LUAD. These data suggest that low-dose selenite should be a potential drug candidate for the treatment of KRAS mutation-positive lung cancer.