Addiction to Golgi-resident PI4P synthesis in chromosome 1q21.3–amplified lung adenocarcinoma cells
Menée à l'aide de lignées cellulaires de cancer du poumon d'origine humaine et à l'aide d'un modèle murin, cette étude met en évidence, dans les cellules cancéreuses avec amplification de la région chromosomique 1q21.3, une dépendance au phosphatidylinositol-4-phosphate synthétisé dans l'appareil de Golgi
Our findings identify a type of oncogene addiction process driven by a lipid that controls prosurvival effector protein secretion. The crosstalk between functionally redundant phosphatidylinositol (PI) 4-kinases maintains addiction and can be targeted with small molecule kinase inhibitors that might be applicable to a genetically defined subset of cancers for which there are no effective targeted therapies.A chromosome 1q21.3 region that is frequently amplified in diverse cancer types encodes phosphatidylinositol (PI)-4 kinase IIIβ (PI4KIIIβ), a key regulator of secretory vesicle biogenesis and trafficking. Chromosome 1q21.3–amplified lung adenocarcinoma (1q-LUAD) cells rely on PI4KIIIβ for Golgi-resident PI-4-phosphate (PI4P) synthesis, prosurvival effector protein secretion, and cell viability. Here, we show that 1q-LUAD cells subjected to prolonged PI4KIIIβ antagonist treatment acquire tolerance by activating an miR-218-5p–dependent competing endogenous RNA network that up-regulates PI4KIIα, which provides an alternative source of Golgi-resident PI4P that maintains prosurvival effector protein secretion and cell viability. These findings demonstrate an addiction to Golgi-resident PI4P synthesis in a genetically defined subset of cancers. Bulk RNA sequencing data have been deposited in the Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo/, GSE120619). All remaining data are included in the article and/or SI Appendix.
Proceedings of the National Academy of Sciences , article en libre accès, 2020