Investigative Ophthalmology & Visual Science Cover Image for Volume 59, Issue 9
July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
PI3K and MEK Signaling and Effects of Kinase Inhibitors in a Retinoblastoma Cell Model
Author Affiliations & Notes
  • Andrew Smith
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Mercy Pawar
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Marcian E Van Dort
    Center for Molecular Imaging, University of Michigan, Ann Arbor, Michigan, United States
    Radiology, University of Michigan, Ann Arbor, Michigan, United States
  • Stefanie Galbán
    Center for Molecular Imaging, University of Michigan, Ann Arbor, Michigan, United States
    Radiology, University of Michigan, Ann Arbor, Michigan, United States
  • Greg Thurber
    Chemical Engineering, University of Michigan, Ann Arbor, Michigan, United States
  • Brian D Ross
    Biological Chemistry, University of Michigan, Ann Arbor, Michigan, United States
    Radiology, University of Michigan, Ann Arbor, Michigan, United States
  • Cagri G Besirli
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Footnotes
    Commercial Relationships   Andrew Smith, None; Mercy Pawar, None; Marcian Van Dort, Sarisa Therapeutics LLC (P); Stefanie Galbán, None; Greg Thurber, None; Brian Ross, Sarisa Therapeutics LLC (P), Sarisa Therapeutics LLC (I); Cagri Besirli, None
  • Footnotes
    Support  March Hoops to Beat Blindness Foundation
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 1629. doi:
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      Andrew Smith, Mercy Pawar, Marcian E Van Dort, Stefanie Galbán, Greg Thurber, Brian D Ross, Cagri G Besirli; PI3K and MEK Signaling and Effects of Kinase Inhibitors in a Retinoblastoma Cell Model. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1629.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To characterize PI3K and MEK signaling pathways in retinoblastoma cells and evaluate the effect of kinase inhibitors, including novel bifunctional kinase inhibitors ST-162 and ST-168 targeting PI3K and MEK signaling pathways simultaneously, on tumor cell survival and proliferation in an in vitro retinoblastoma cell model.

Methods : Y79, a human retinoblastoma cell line derived from a primary tumor, was treated with a PI3K inhibitor ZSTK474, MEK inhibitor PD0325901, ZSTK474 & PD0325901 combined or novel bifunctional inhibitors of PI3K/MEK, ST-162 and ST-168. Cells were incubated at concentrations of 5mM, 10mM, 25mM, 50mM, and 100mM for 24 hours and western blots performed to determine PI3K and MEK activity. Survival of Y79 cells was assessed in the presence of PI3K and MEK inhibitors up to 72 hours.

Results : PI3K inhibition by ZSTK474 led to increased cell death by 72 hours. In contrast, MEK inhibition by PD0325901 had little affect on cell survival. ZSTK474-mediated cell death was reversed by MEK inhibition in cells treated with the ZSTK474 and PD0325901 cocktail. Bifunctional inhibitors ST-162 and ST-168 demonstrated a mixed effect on Y79 survival.

Conclusions : PI3K signaling is important for the survival of Y79 retinoblastoma cells. Toxicity of PI3K inhibition is reversed by MEK inhibitor PD0325901. Novel bifunctional PI3K/MEK inhibitors ST-162 and ST-168 demonstrate a mixed effect on the survival of retinoblastoma cells, likely secondary to the variable potency of these novel agents against PI3K and MEK.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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