Notice: Users may be experiencing issues with displaying some pages on stanfordhealthcare.org. We are working closely with our technical teams to resolve the issue as quickly as possible. Thank you for your patience.
 

Learn about the flu shot, COVID-19 vaccine, and our masking policy »

Stanford Health Care

PI4KIIIß is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma. Science translational medicine Tan, X. n., Banerjee, P. n., Pham, E. A., Rutaganira, F. U., Basu, K. n., Bota-Rabassedas, N. n., Guo, H. F., Grzeskowiak, C. L., Liu, X. n., Yu, J. n., Shi, L. n., Peng, D. H., Rodriguez, B. L., Zhang, J. n., Zheng, V. n., Duose, D. Y., Solis, L. M., Mino, B. n., Raso, M. G., Behrens, C. n., Wistuba, I. I., Scott, K. L., Smith, M. n., Nguyen, K. n., Lam, G. n., Choong, I. n., Mazumdar, A. n., Hill, J. L., Gibbons, D. L., Brown, P. H., Russell, W. K., Shokat, K. n., Creighton, C. J., Glenn, J. S., Kurie, J. M. 2020; 12 (527)

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 IIIß (PI4KIIIß). Molecular, biochemical, and cell biological studies show that PI4KIIIß-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. PI4KIIIß-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 PI4KIIIß antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIß-dependent secretion for cancer cell survival and tumor progression.

View details for DOI 10.1126/scitranslmed.aax3772

View details for PubMedID 31969487