PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma.
Xiaochao TanPriyam BanerjeeEdward A PhamFlorentine U N RutaganiraKaustabh BasuNeus Bota-RabassedasHou-Fu GuoCaitlin L GrzeskowiakXin LiuJiang YuLei ShiDavid H PengB Leticia RodriguezJiaqi ZhangVeronica ZhengDzifa Y DuoseLuisa Maren Solis SotoBarbara MinoMaria Gabriela RasoCarmen BehrensIgnacio I WistubaKenneth L ScottMark SmithKhanh NguyenGrace LamIngrid ChoongAbhijit MazumdarJamal L HillDon L GibbonsPowel H BrownWilliam K RussellKevan M ShokatChad J CreightonJeffrey S GlennPublished in: Science translational medicine (2021)
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.