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 Behrens; Ignacio 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

doi:10.1126/scitranslmed.aax3772

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

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › peer-review

49 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 language	English (US)
Article number	eaax3772
Journal	Science Translational Medicine
Volume	12
Issue number	527
DOIs	https://doi.org/10.1126/scitranslmed.aax3772
State	Published - Jan 22 2020

ASJC Scopus subject areas

General Medicine

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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), Article eaax3772. https://doi.org/10.1126/scitranslmed.aax3772

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, Leticia Rodriguez, B, 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 2020, 'PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma', Science Translational Medicine, vol. 12, no. 527, eaax3772. https://doi.org/10.1126/scitranslmed.aax3772

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title = "PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma",

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.",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",

year = "2020",

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doi = "10.1126/scitranslmed.aax3772",

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T1 - PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma

AU - Tan, Xiaochao

AU - Banerjee, Priyam

AU - Pham, Edward A.

AU - Rutaganira, Florentine U.N.

AU - Basu, Kaustabh

AU - Bota-Rabassedas, Neus

AU - Guo, Hou Fu

AU - Grzeskowiak, Caitlin L.

AU - Liu, Xin

AU - Yu, Jiang

AU - Shi, Lei

AU - Peng, David H.

AU - Leticia Rodriguez, B.

AU - Zhang, Jiaqi

AU - Zheng, Veronica

AU - Duose, Dzifa Y.

AU - Solis, Luisa M.

AU - Mino, Barbara

AU - Raso, Maria Gabriela

AU - Behrens, Carmen

AU - Wistuba, Ignacio I.

AU - Scott, Kenneth L.

AU - Smith, Mark

AU - Nguyen, Khanh

AU - Lam, Grace

AU - Choong, Ingrid

AU - Mazumdar, Abhijit

AU - Hill, Jamal L.

AU - Gibbons, Don L.

AU - Brown, Powel H.

AU - Russell, William K.

AU - Shokat, Kevan

AU - Creighton, Chad J.

AU - Glenn, Jeffrey S.

AU - Kurie, Jonathan M.

PY - 2020/1/22

Y1 - 2020/1/22

N2 - 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.

AB - 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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DO - 10.1126/scitranslmed.aax3772

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C2 - 31969487

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SN - 1946-6234

VL - 12

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 527

M1 - eaax3772

ER -

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

Abstract

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