C-ATF6 improves EGFR tyrosine kinase inhibitor sensitivity in non-small cell lung cancer via modulation of the calcium homeostasis network.

Osimertinib (Osi) is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), and its clinical efficacy is limited due to the emergence of resistance. We found that parental cells undergo a drug-tolerant persister (DTP) state before ultimately achieving acquired resistance. In this study, we restored the specifically dysregulated circular RNA (cATF6) in the DTP state and used it in combination with Osimertinib, finding that it could significantly synergistically target DTP tumor cells. Mechanistically, it mainly disrupted the balance of Ca2+, ultimately leading to the death of DTP cells due to Ca2+ overload. This study reveals the impact of cATF6 on the dynamic balance of calcium ions, which may bring new strategies for epidermal growth factor receptor inhibitors (EGFR-TKIs) to eradicate DTP. Overall design: HCC827 cells were treated with DMSO or osimertinib for 10 days and subjected to whole transcriptome sequencing. Transcriptome sequencing was performed on HCC827 cells in the EV or overexpression of circRNA-cATF6, as well as in the parental, DTP state, and acquired resistant state.