[Research Articles] PI4KIII{beta} is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma

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.

Source: Science Translational Medicine - January 21, 2020 Category: Biomedical Science Authors: Tan, X., Banerjee, P., Pham, E. A., Rutaganira, F. U. N., Basu, K., Bota-Rabassedas, N., Guo, H.-F., Grzeskowiak, C. L., Liu, X., Yu, J., Shi, L., Peng, D. H., Rodriguez, B. L., Zhang, J., Zheng, V., Duose, D. Y., Solis, L. M., Mino, B., Raso, M. G., Behr Tags: Research Articles Source Type: research