The G protein‐coupled receptor GPR 89 A is a novel potential therapeutic target to overcome cisplatin resistance in NSCLC Calu1 cells

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Lung cancer is the most frequently diagnosed cancer type worldwide and is characterised by its high metastatic potential. Standard therapy for nonsmall cell lung cancer (NSCLC) cases includes chemotherapy with the platinum-based chemotherapeutic agent cisplatin. Although lung cancer cases respond well to cisplatin at the beginning of treatment, ~ 60% develop chemotherapy resistance during this process. In this study, a genome-wide CRISPR-Cas9-based genetic screening approach was employed to identify genes that cisplatin-resistant NSCLC Calu1 cells are more addicted to than sensitive cells. Cisplatin-resistant Calu1 cells were generated by the dose escalation method, and genome-wide CRISPR-Cas9-based genetic screening was performed with the Brunello CRISPR knockout library. Bioinformatics analyses of the obtained next-generation sequencing data revealed 63 potential candidate genes responsible for cisplatin resistance, including G protein-coupled receptor 89A (GPR89A), Poly(U) binding splicing factor 60 (PUF60), NBAS subunit of NRZ tethering complex (NBAS) and GrpE like 1, mitochondrial (GRPEL1). The GPR89A protein is located in the Golgi cisterna and Golgi-associated vesicle membrane, enables voltage-gated anion channel activity, and is involved in intracellular pH reduction. Functional studies carried out with GPR89A-knockout cisplatin-resistant Calu1 cells resulted in cell cycle arrest in the G2/M phase and increased polyploidy, and also prevented colony formation and cell migration. Cisplatin treatment, on the other hand, resulted in increased cell death by apoptosis upon cell cycle arrest in the S phase. In conclusion, this is the first study that identified GPR89A as a potential therapeutic target to overcome cisplatin resistance in NSCLC Calu1 cells.

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