Addiction to Golgi-resident PI4P synthesis in chromosome 1q21.3–amplified lung adenocarcinoma cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-06, Vol.118 (25), p.1-9
• Main Authors: Shi, Lei, Tan, Xiaochao, Liu, Xin, Yu, Jiang, Bota-Rabassedas, Neus, Niu, Yichi, Luo, Jiayi, Xi, Yuanxin, Zong, Chenghang, Creighton, Chad J., Glenn, Jeffrey S., Wang, Jing, Kurie, Jonathan M.
• Format: Article
• Language: English
• Subjects: Addictions; Adenocarcinoma; Amplification; Biological Sciences; Cancer; Cell viability; Chromosome 1; Chromosomes; Drug tolerance; Golgi apparatus; Kinases; Lungs; Protein biosynthesis; Proteins; Secretion; Synthesis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2023537118

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.