Δευτέρα 27 Ιανουαρίου 2020

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

PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma.:

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

Sci Transl Med. 2020 Jan 22;12(527):

Authors: Tan X, Banerjee P, Pham EA, Rutaganira FUN, Basu K, Bota-Rabassedas N, Guo HF, Grzeskowiak CL, Liu X, Yu J, Shi L, Peng DH, Rodriguez BL, Zhang J, Zheng V, Duose DY, Solis LM, Mino B, Raso MG, Behrens C, Wistuba II, Scott KL, Smith M, Nguyen K, Lam G, Choong I, Mazumdar A, Hill JL, Gibbons DL, Brown PH, Russell WK, Shokat K, Creighton CJ, Glenn JS, Kurie JM

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.

PMID: 31969487 [PubMed - in process]

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