Targeting primary and metastatic uveal melanoma with a G protein inhibitor

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

doi:10.1016/j.jbc.2021.100403

Cited by 29 publications

(47 citation statements)

References 52 publications

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“…FR also inhibited the growth and proliferative signaling of UM cells containing oncogenic Gα q/11 proteins [ 118 ]. Additional studies investigating similar effects of FR emerged around the same time [ 93 , 119 , 120 , 121 ] while research involving YM treatment of UM have followed [ 95 , 122 ].…”

Section: Direct Targeting Of Gα Q/11mentioning

confidence: 99%

“…YM and FR show significant inhibitory activity against every mutant Gα q/11 variant found in UM in transfected HEK293 cell-based experiments [ 121 , 122 ]. Both compounds selectively inhibit cell growth and promote growth arrest of UM cells harboring oncogenic Gα q/11 , as well as oncogenic cysteinyl leukotriene receptor 2 (CysLT 2 R L129Q ) [ 93 , 95 , 118 , 119 , 120 , 121 , 122 ]. FR, and likely YM, target both primary and metastatic cells from UM tumors [ 121 ].…”

Section: Direct Targeting Of Gα Q/11mentioning

confidence: 99%

“…Both compounds selectively inhibit cell growth and promote growth arrest of UM cells harboring oncogenic Gα q/11 , as well as oncogenic cysteinyl leukotriene receptor 2 (CysLT 2 R L129Q ) [ 93 , 95 , 118 , 119 , 120 , 121 , 122 ]. FR, and likely YM, target both primary and metastatic cells from UM tumors [ 121 ]. YM and FR selectively inhibit the essential oncogenic signaling of Gα q/11 mutant UM cells.…”

Section: Direct Targeting Of Gα Q/11mentioning

confidence: 99%

“…YM and FR selectively inhibit the essential oncogenic signaling of Gα q/11 mutant UM cells. Treatment of UM cells with these G q/11 inhibitors abolishes MAPK signaling, suppresses Akt activation, prevents YAP localization to the nucleus, and represses FAK activation [ 93 , 95 , 118 , 119 , 120 , 121 , 122 ]. Class one UM cells (wild-type for BAP1) begin to express melan-A at the plasma membrane and gain pigmentation when treated with low nanomolar concentrations of FR [ 118 , 119 , 121 ].…”

Section: Direct Targeting Of Gα Q/11mentioning

confidence: 99%

“…Treatment of UM cells with these G q/11 inhibitors abolishes MAPK signaling, suppresses Akt activation, prevents YAP localization to the nucleus, and represses FAK activation [ 93 , 95 , 118 , 119 , 120 , 121 , 122 ]. Class one UM cells (wild-type for BAP1) begin to express melan-A at the plasma membrane and gain pigmentation when treated with low nanomolar concentrations of FR [ 118 , 119 , 121 ]. This suggests FR can induce a redifferentiation of these cancer cells, possibly by decreasing G q/11 activity to a level closer to that of a normal melanocyte.…”

Section: Direct Targeting Of Gα Q/11mentioning

confidence: 99%

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Targeting Oncogenic Gαq/11 in Uveal Melanoma

Lapadula

Benovic

2021

Cancers

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Uveal melanoma is the most common intraocular cancer in adults and arises from the transformation of melanocytes in the uveal tract. While treatment of the primary tumor is often effective, 36–50% of patients develop metastatic disease primarily to the liver. While various strategies have been used to treat the metastatic disease, there remain no effective treatments that improve survival. Significant insight has been gained into the pathways that are altered in uveal melanoma, with mutually exclusive activating mutations in the GNAQ and GNA11 genes being found in over 90% of patients. These genes encode the alpha subunits of the hetetrotrimeric G proteins, Gq and G11, and mutations result in activation of several important signaling pathways, including phospholipase C and activation of the transcription factor YAP. In this review, we discuss current efforts to target various signaling pathways in the treatment of uveal melanoma including recent efforts to target Gq and G11 in mouse models. While selective targeting of Gq and G11 provides a potential therapeutic strategy to treat uveal melanoma, it is evident that improved inhibitors and methods of delivery are needed.

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Section: Direct Targeting Of Gα Q/11mentioning

confidence: 99%

Section: Direct Targeting Of Gα Q/11mentioning

confidence: 99%

Section: Direct Targeting Of Gα Q/11mentioning

confidence: 99%

Section: Direct Targeting Of Gα Q/11mentioning

confidence: 99%

Section: Direct Targeting Of Gα Q/11mentioning

confidence: 99%

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Targeting Oncogenic Gαq/11 in Uveal Melanoma

Lapadula

Benovic

2021

Cancers

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Promoter‐Driven Overexpression in Chromobacterium vaccinii Facilitates Access to FR900359 and Yields Novel Low Abundance Analogs

Pistorius

Buntin

Weber

et al. 2021

Chemistry A European J

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Access to the cyclic depsipeptide FR900359 (FR), a selective Gq/11 protein inhibitor of high pharmacological interest and a potential lead molecule for targeted therapy of cancers with oncogenic GNAQ or GNA11 mutations (encoding Gq and G11 respectively), has been challenging ever since its initial discovery more than three decades ago. The recent discovery of Chromobacterium vaccinii as a cultivable FR producer enables the development of approaches leading to a high‐yielding, scalable and sustainable biotechnological process for production of FR, thereby removing this bottleneck. Here we characterize different promoters in exchange of the native promoter of the FR assembly line, resulting in an overexpression mutant with significantly increased production of FR. Thereby, the isolation and structure elucidation of novel FR analogs of low abundance is enabled. Further, we explore the antiproliferative activities of fifteen chromodepsins against uveal melanoma cell lines harboring Gq/11 mutations and characterize the major metabolite of FR formed in plasma.

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