Direct Inhibition of Oncogenic Gq/11 in Uveal Melanoma
Abstract
Uveal melanoma (UM) is the most common intraocular tumor in adults and often metastasizes to the liver, leaving patients with limited treatment options and short survival time. While activating mutations in the G proteins, Gαq and Gα11, are the major drivers of metastasis, therapeutic intervention of downstream Gαq/11 targets has been unsuccessful in treating UM, possibly due to alternative signaling pathways and/or resistance mechanisms. In this thesis work, we provide evidence via fluorescent DNA intercalation, flow cytometry, and 3D Matrigel culture that oncogenic Gq/11 inhibition by YM-254890 (YM) and FR900359 (FR) leads to the inhibited growth and cell cycle arrest of primary and metastatic UM cells. We utilized traditional immunoblotting, fluorescence microscopy, and reverse-phase protein array analysis to reveal oncogenic Gq/11 inhibition downregulates the aberrant signaling of multiple pathways involved in UM pathogenesis. Additionally, we have identified insulin-like growth factor 1 (IGF1) signaling through the IGF1 receptor (IGF1R) as a potential means of resistance to Gq/11 inhibition in UM cells. We further demonstrate that Gq/11 inhibition by YM in combination with the inhibition of IGF1R by linsitinib acts synergistically to inhibit UM cell proliferation and inhibits downstream signaling in a combinatorial manner. Using immunodeficient NOD scid gamma (NSG) mice we reveal that this combination treatment significantly inhibits the growth of metastatic UM tumors in the liver. This is significant due to the hepatic tropism of UM. This supports the growing notion that a combinatorial approach will be necessary to treat UM patients with Gq/11 inhibitors. Together, this work illustrates the potential use of Gq/11 inhibitors and continued difficulties in treating metastatic UM.
Subject Area
Biochemistry|Biology|Oncology
Recommended Citation
Lapadula, Dominic J, "Direct Inhibition of Oncogenic Gq/11 in Uveal Melanoma" (2022). ProQuest ETD Collection - Thomas Jefferson University. AAI29208573.
https://jdc.jefferson.edu/dissertations/AAI29208573
