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.

染色体 1q21.3 区域在不同的癌症类型中经常扩增，编码磷脂酰肌醇 (PI)-4 激酶 IIIβ (PI4KIIIβ)，这是分泌囊泡生物发生和运输的关键调节因子。染色体 1q21.3 扩增的肺腺癌 (1q-LUAD) 细胞依赖 PI4KIIIβ 进行高尔基体 PI-4-磷酸 (PI4P) 合成、促存活效应蛋白分泌和细胞活力。在这里，我们表明，经过长期 PI4KIIIβ 拮抗剂治疗的 1q-LUAD 细胞通过激活 miR-218-5p 依赖性竞争性内源性 RNA 网络来获得耐受性，该网络上调 PI4KIIα，这提供了维持促存活的高尔基体 PI4P 的替代来源效应蛋白分泌和细胞活力。这些发现表明在基因定义的癌症子集中对高尔基体 PI4P 合成上瘾。