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

Area of Science:

• Oncology
• Molecular Biology
• Trace Element Research

Background:

• Selenium is an essential trace element with known pro-apoptotic and DNA demethylation properties.
• Ferroptosis, a novel cell death pathway, is explored for cancer treatment and overcoming drug resistance.
• The role of selenium in targeting cancer cells with specific oncogenic alterations remains largely unelucidated.

Purpose of the Study:

• To investigate the effects of sodium selenite on apoptosis, ferroptosis, and DNA methylation in lung adenocarcinoma cell lines.
• To evaluate the synergistic potential of selenite with targeted therapies like osimertinib and adagrasib.
• To explore the underlying mechanisms of selenite-induced cell death in EGFR- and KRAS-mutant lung cancer.

Main Methods:

• Treatment of EGFR-mutant (H1975) and KRAS-mutant (H358) lung adenocarcinoma cell lines with sodium selenite.
• Assessment of cell apoptosis, ferroptosis, and DNA methylation.
• Evaluation of selenite's interaction with osimertinib (EGFR inhibitor) and adagrasib (KRAS inhibitor).

Main Results:

• Selenite demonstrated dual apoptotic and ferroptotic activity in lung cancer cells, linked to the p38-ATF4-DDIT3 pathway.
• Ferroptosis induction was more pronounced in EGFR-mutant H1975 cells compared to KRAS-mutant H358 cells.
• Low-dose selenite exhibited synergistic effects with osimertinib in EGFR-mutant cells and adagrasib in KRAS-mutant cells, with stronger synergy in H1975 cells.

Conclusions:

• Selenium compounds show potential as therapeutic agents for lung cancer, particularly in cases with EGFR or KRAS mutations.
• Selenite's ability to induce both apoptosis and ferroptosis, along with its synergistic effects with targeted therapies, highlights its therapeutic promise.
• Further research into selenium's mechanisms and clinical applications in mutant lung cancer is warranted.