Targeting primary and metastatic uveal melanoma with a G protein inhibitor

Michael D Onken,Carol M Makepeace,Kevin M Kaltenbronn,Joelle Choi,Leonel Hernandez-Aya,Katherine N Weilbaecher,Kisha D Piggott,P Kumar Rao,Carla M Yuede,Alethia J Dixon,Patrick Osei-Owusu,John A Cooper,Kendall J Blumer

doi:10.1016/j.jbc.2021.100403

Michael D Onken, Carol M Makepeace + Show 11 more

Open Access

https://doi.org/10.1016/j.jbc.2021.100403

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Abstract

Uveal melanoma (UM) is the most common intraocular tumor in adults. Nearly half of UM patients develop metastatic disease and often succumb within months because effective therapy is lacking. A novel therapeutic approach has been suggested by the discovery that UM cell lines driven by mutant constitutively active Gq or G11 can be targeted by FR900359 (FR) or YM-254890, which are bioavailable, selective inhibitors of the Gq/11/14 subfamily of heterotrimeric G proteins. Here, we have addressed the therapeutic potential of FR for UM. We found that FR inhibited all oncogenic Gq/11 mutants reported in UM. FR arrested growth of all Gq/11-driven UM cell lines tested, but induced apoptosis only in a few. Similarly, FR inhibited growth of, but did not efficiently kill, UM tumor cells from biopsies of primary or metastatic tumors. FR evoked melanocytic redifferentiation of UM tumor cells with low (class 1), but not high (class 2), metastatic potential. FR administered systemically below its LD50 strongly inhibited growth of PDX-derived class 1 and class 2 UM tumors in mouse xenograft models and reduced blood pressure transiently. FR did not regress xenografted UM tumors or significantly affect heart rate, liver function, hematopoiesis, or behavior. These results indicated the existence of a therapeutic window in which FR can be explored for treating UM and potentially other diseases caused by constitutively active Gq/11.

Highlights

Uveal melanoma (UM) is the most common intraocular tumor in adults
Recent studies have shown that YM or FR (YM/FR) can inhibit growth of UM tumors in mouse xenograft models [19, 30], questions left unanswered are whether YM/FR can target primary and/or metastatic UM tumor cells from patients, whether YM/FR responsiveness is affected by tumor-intrinsic factors, including the type of oncogenic Gq/11 mutation, tumor class or metastatic potential, or whether systemic administration of YM/FR at levels sufficient to target UM tumor xenografts has serious
We found that four UM cell lines (Fig. 1B) driven by three different oncogenic Gq/11 mutants responded to FR in quantitatively or qualitatively different ways

Summary

Introduction

Uveal melanoma (UM) is the most common intraocular tumor in adults. Nearly half of UM patients develop metastatic disease and often succumb within months because effective therapy is lacking. Two-dimensional t-SNE plots of single-cell scRNAseq data are shown for each of the three indicated primary UM tumor samples obtained after enucleation, and treated 7 days with vehicle or FR (100 nM). For the nine FR-responsive UM tumor samples, which included class 1 and class 2 primary tumors and a liver metastasis, we found that FR caused similar directional effects on gene expression, as revealed by unsupervised principal component analysis (PCA) (Fig. 3C).

Results

Conclusion