Research ArticleCancer

PI4KIIIβ is a therapeutic target in chromosome 1q–amplified lung adenocarcinoma

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Science Translational Medicine  22 Jan 2020:
Vol. 12, Issue 527, eaax3772
DOI: 10.1126/scitranslmed.aax3772

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The secrets of malignant secretion

Cancer cells produce and secrete a variety of proteins that promote tumorigenesis, in a process known as malignant secretion. Tan et al. identified a region of chromosome 1 that is often amplified in cancer and plays a key role in malignant secretion. In particular, the authors discovered a mechanism by which a Golgi-associated enzyme called PI4KIIIβ promotes secretion of proteins involved in lung cancer survival and metastasis. The authors identified and optimized chemical inhibitors of PI4KIIIβ and then tested their effectiveness at blocking malignant secretion and reducing cancer cells’ invasiveness in vitro and in multiple mouse models of cancer.

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.

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