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

Xiaochao Tan, Priyam Banerjee, Edward A. Pham, Florentine U.N. Rutaganira, Kaustabh Basu, Neus Bota-Rabassedas, Hou Fu Guo, Caitlin L. Grzeskowiak, Xin Liu, Jiang Yu, Lei Shi, David H. Peng, B. Leticia Rodriguez, Jiaqi Zhang, Veronica Zheng, Dzifa Y. Duose, Luisa M. Solis, Barbara Mino, Maria Gabriela Raso, Carmen BehrensIgnacio I. Wistuba, Kenneth L. Scott, Mark Smith, Khanh Nguyen, Grace Lam, Ingrid Choong, Abhijit Mazumdar, Jamal L. Hill, Don L. Gibbons, Powel H. Brown, William K. Russell, Kevan Shokat, Chad J. Creighton, Jeffrey S. Glenn, Jonathan M. Kurie

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Article numbereaax3772
JournalScience Translational Medicine
Volume12
Issue number527
DOIs
StatePublished - Jan 22 2020

ASJC Scopus subject areas

  • Medicine(all)

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    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., Leticia Rodriguez, B., Zhang, J., Zheng, V., Duose, D. Y., Solis, L. M., Mino, B., Raso, M. G., ... Kurie, J. M. (2020). PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma. Science Translational Medicine, 12(527), [eaax3772]. https://doi.org/10.1126/scitranslmed.aax3772