학술논문
PI4KIIIβ is a therapeutic target in chromosome 1q–amplified lung adenocarcinoma
Document Type
article
Author
Tan, Xiaochao; Banerjee, Priyam; Pham, Edward A; Rutaganira, Florentine UN; Basu, Kaustabh; Bota-Rabassedas, Neus; Guo, Hou-Fu; Grzeskowiak, Caitlin L; Liu, Xin; Yu, Jiang; Shi, Lei; Peng, David H; Rodriguez, B Leticia; Zhang, Jiaqi; Zheng, Veronica; Duose, Dzifa Y; Solis, Luisa M; Mino, Barbara; Raso, Maria Gabriela; Behrens, Carmen; Wistuba, Ignacio I; Scott, Kenneth L; Smith, Mark; Nguyen, Khanh; Lam, Grace; Choong, Ingrid; Mazumdar, Abhijit; Hill, Jamal L; Gibbons, Don L; Brown, Powel H; Russell, William K; Shokat, Kevan; Creighton, Chad J; Glenn, Jeffrey S; Kurie, Jonathan M
Source
Science Translational Medicine. 12(527)
Subject
Language
Abstract
Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)-dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIβ-dependent secretion for cancer cell survival and tumor progression.