Co-Targeting FASN and mTOR Suppresses Uveal Melanoma Growth

Anna Han; Dzmitry Mukha; Vivian Chua; Timothy J. Purwin; Manoela Tiago; Bhavik Modasia; Usman Baqai; Jenna L. Aumiller; Nelisa Bechtel; Emily Hunter; Meggie Danielson; Mizue Terai; Philip B. Wedegaertner; Takami Sato; Solange Landreville; Michael A. Davies; Stefan Kurtenbach; J. William Harbour; Zachary T. Schug; Andrew E. Aplin

doi:10.3390/cancers15133451

Co-Targeting FASN and mTOR Suppresses Uveal Melanoma Growth

Anna Han, Dzmitry Mukha, Vivian Chua, Timothy J. Purwin, Manoela Tiago, Bhavik Modasia, Usman Baqai, Jenna L. Aumiller, Nelisa Bechtel, Emily Hunter, Meggie Danielson, Mizue Terai, Philip B. Wedegaertner, Takami Sato, Solange Landreville, Michael A. Davies, Stefan Kurtenbach, J. William Harbour, Zachary T. Schug, Andrew E. Aplin

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

Abstract

Uveal melanoma (UM) displays a high frequency of metastasis; however, effective therapies for metastatic UM are limited. Identifying unique metabolic features of UM may provide a potential targeting strategy. A lipid metabolism protein expression signature was induced in a normal choroidal melanocyte (NCM) line transduced with GNAQ (Q209L), a driver in UM growth and development. Consistently, UM cells expressed elevated levels of fatty acid synthase (FASN) compared to NCMs. FASN upregulation was associated with increased mammalian target of rapamycin (mTOR) activation and sterol regulatory element-binding protein 1 (SREBP1) levels. FASN and mTOR inhibitors alone significantly reduced UM cell growth. Concurrent inhibition of FASN and mTOR further reduced UM cell growth by promoting cell cycle arrest and inhibiting glucose utilization, TCA cycle metabolism, and de novo fatty acid biosynthesis. Our findings indicate that FASN is important for UM cell growth and co-inhibition of FASN and mTOR signaling may be considered for treatment of UM.

Original language	English (US)
Article number	3451
Journal	Cancers
Volume	15
Issue number	13
DOIs	https://doi.org/10.3390/cancers15133451
State	Published - Jul 2023
Externally published	Yes

Keywords

GNAQ
fatty acid synthase
mTOR pathway
metabolic inhibition
uveal melanoma

ASJC Scopus subject areas

Oncology
Cancer Research

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10.3390/cancers15133451

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Han, A., Mukha, D., Chua, V., Purwin, T. J., Tiago, M., Modasia, B., Baqai, U., Aumiller, J. L., Bechtel, N., Hunter, E., Danielson, M., Terai, M., Wedegaertner, P. B., Sato, T., Landreville, S., Davies, M. A., Kurtenbach, S., Harbour, J. W., Schug, Z. T., & Aplin, A. E. (2023). Co-Targeting FASN and mTOR Suppresses Uveal Melanoma Growth. Cancers, 15(13), Article 3451. https://doi.org/10.3390/cancers15133451

Han, A, Mukha, D, Chua, V, Purwin, TJ, Tiago, M, Modasia, B, Baqai, U, Aumiller, JL, Bechtel, N, Hunter, E, Danielson, M, Terai, M, Wedegaertner, PB, Sato, T, Landreville, S, Davies, MA, Kurtenbach, S, Harbour, JW, Schug, ZT & Aplin, AE 2023, 'Co-Targeting FASN and mTOR Suppresses Uveal Melanoma Growth', Cancers, vol. 15, no. 13, 3451. https://doi.org/10.3390/cancers15133451

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title = "Co-Targeting FASN and mTOR Suppresses Uveal Melanoma Growth",

abstract = "Uveal melanoma (UM) displays a high frequency of metastasis; however, effective therapies for metastatic UM are limited. Identifying unique metabolic features of UM may provide a potential targeting strategy. A lipid metabolism protein expression signature was induced in a normal choroidal melanocyte (NCM) line transduced with GNAQ (Q209L), a driver in UM growth and development. Consistently, UM cells expressed elevated levels of fatty acid synthase (FASN) compared to NCMs. FASN upregulation was associated with increased mammalian target of rapamycin (mTOR) activation and sterol regulatory element-binding protein 1 (SREBP1) levels. FASN and mTOR inhibitors alone significantly reduced UM cell growth. Concurrent inhibition of FASN and mTOR further reduced UM cell growth by promoting cell cycle arrest and inhibiting glucose utilization, TCA cycle metabolism, and de novo fatty acid biosynthesis. Our findings indicate that FASN is important for UM cell growth and co-inhibition of FASN and mTOR signaling may be considered for treatment of UM.",

keywords = "GNAQ, fatty acid synthase, mTOR pathway, metabolic inhibition, uveal melanoma",

author = "Anna Han and Dzmitry Mukha and Vivian Chua and Purwin, {Timothy J.} and Manoela Tiago and Bhavik Modasia and Usman Baqai and Aumiller, {Jenna L.} and Nelisa Bechtel and Emily Hunter and Meggie Danielson and Mizue Terai and Wedegaertner, {Philip B.} and Takami Sato and Solange Landreville and Davies, {Michael A.} and Stefan Kurtenbach and Harbour, {J. William} and Schug, {Zachary T.} and Aplin, {Andrew E.}",

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doi = "10.3390/cancers15133451",

language = "English (US)",

volume = "15",

journal = "Cancers",

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AU - Han, Anna

AU - Mukha, Dzmitry

AU - Chua, Vivian

AU - Purwin, Timothy J.

AU - Tiago, Manoela

AU - Modasia, Bhavik

AU - Baqai, Usman

AU - Aumiller, Jenna L.

AU - Bechtel, Nelisa

AU - Hunter, Emily

AU - Danielson, Meggie

AU - Terai, Mizue

AU - Wedegaertner, Philip B.

AU - Sato, Takami

AU - Landreville, Solange

AU - Davies, Michael A.

AU - Kurtenbach, Stefan

AU - Harbour, J. William

AU - Schug, Zachary T.

AU - Aplin, Andrew E.

PY - 2023/7

Y1 - 2023/7

N2 - Uveal melanoma (UM) displays a high frequency of metastasis; however, effective therapies for metastatic UM are limited. Identifying unique metabolic features of UM may provide a potential targeting strategy. A lipid metabolism protein expression signature was induced in a normal choroidal melanocyte (NCM) line transduced with GNAQ (Q209L), a driver in UM growth and development. Consistently, UM cells expressed elevated levels of fatty acid synthase (FASN) compared to NCMs. FASN upregulation was associated with increased mammalian target of rapamycin (mTOR) activation and sterol regulatory element-binding protein 1 (SREBP1) levels. FASN and mTOR inhibitors alone significantly reduced UM cell growth. Concurrent inhibition of FASN and mTOR further reduced UM cell growth by promoting cell cycle arrest and inhibiting glucose utilization, TCA cycle metabolism, and de novo fatty acid biosynthesis. Our findings indicate that FASN is important for UM cell growth and co-inhibition of FASN and mTOR signaling may be considered for treatment of UM.

AB - Uveal melanoma (UM) displays a high frequency of metastasis; however, effective therapies for metastatic UM are limited. Identifying unique metabolic features of UM may provide a potential targeting strategy. A lipid metabolism protein expression signature was induced in a normal choroidal melanocyte (NCM) line transduced with GNAQ (Q209L), a driver in UM growth and development. Consistently, UM cells expressed elevated levels of fatty acid synthase (FASN) compared to NCMs. FASN upregulation was associated with increased mammalian target of rapamycin (mTOR) activation and sterol regulatory element-binding protein 1 (SREBP1) levels. FASN and mTOR inhibitors alone significantly reduced UM cell growth. Concurrent inhibition of FASN and mTOR further reduced UM cell growth by promoting cell cycle arrest and inhibiting glucose utilization, TCA cycle metabolism, and de novo fatty acid biosynthesis. Our findings indicate that FASN is important for UM cell growth and co-inhibition of FASN and mTOR signaling may be considered for treatment of UM.

KW - GNAQ

KW - fatty acid synthase

KW - mTOR pathway

KW - metabolic inhibition

KW - uveal melanoma

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Co-Targeting FASN and mTOR Suppresses Uveal Melanoma Growth

Abstract

Keywords

ASJC Scopus subject areas

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