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Inhibition of NRAS Signaling in Melanoma through Direct Depalmitoylation Using Amphiphilic Nucleophiles.

ABSTRACT: Activating mutations in the small GTPase NRAS are responsible for driving tumor growth in several cancers. Unfortunately, the development of NRAS inhibitors has proven difficult due to the lack of hydrophobic binding pockets on the protein's surface. To overcome this limitation, we chose to target the post-translational S-palmitoyl modification of NRAS, which is required for its signaling activity. Utilizing an amphiphile-mediated depalmitoylation (AMD) strategy, we demonstrate the ability to directly cleave S-palmitoyl groups from NRAS and inhibit its function. C8 alkyl cysteine causes a dose-dependent decrease in NRAS palmitoylation and inhibits downstream signaling in melanoma cells with an activating mutation in NRAS. This compound reduces cell growth in NRAS-driven versus non-NRAS-driven melanoma lines and inhibits tumor progression in an NRAS-mutated melanoma xenograft mouse model. Our work demonstrates that AMD can effectively suppress NRAS activity and could represent a promising new avenue for discovering lead compounds for treatment of NRAS-driven cancers.

SUBMITTER: Vora HD

PROVIDER: S-EPMC7556697 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Inhibition of NRAS Signaling in Melanoma through Direct Depalmitoylation Using Amphiphilic Nucleophiles.

Vora Hetika D HD Johnson Mai M Brea Roberto J RJ Rudd Andrew K AK Devaraj Neal K NK

ACS chemical biology 20200713 8

Activating mutations in the small GTPase NRAS are responsible for driving tumor growth in several cancers. Unfortunately, the development of NRAS inhibitors has proven difficult due to the lack of hydrophobic binding pockets on the protein's surface. To overcome this limitation, we chose to target the post-translational S-palmitoyl modification of NRAS, which is required for its signaling activity. Utilizing an amphiphile-mediated depalmitoylation (AMD) strategy, we demonstrate the ability to di ...[more]

PMID: 32568509

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Project description:Simple Summary Targeted radionuclide therapy (TRT) aims to selectively deliver radioactive molecules to tumor cells. For this purpose, we deliver iodine-131 ([131I]) to melanoma cells by using our laboratory-developed melanin specific radiotracer, the ICF01012. Approximately 50% and 20%–30% of human melanomas have activating mutation in BRAF or NRAS genes, respectively. These mutations lead to a constitutive activation of the MAPK/ERK pathway, which is known to be involved in tumor cells’ radioresistance. In this work, we showed using 3D in vitro tumor models, an additive efficiency of combining [131I]ICF01012-TRT and MAPK/ERK inhibitors in BRAF- and NRAS-mutant melanoma cells. In mice bearing NRASQ61K-mutated melanoma, TRT induced an impressive decrease in tumor growth, as well as a highly extended survival. Additionally, we showed that TRT reduces the metastatic capacity of melanoma, especially through lymph-node dissemination. These results are therefore of great interest, especially for patients with NRAS-mutant metastatic melanoma who currently lack specific efficient therapies. Abstract Purpose: To assess the efficiency of targeted radionuclide therapy (TRT), alone or in combination with MEK inhibitors (MEKi), in melanomas harboring constitutive MAPK/ERK activation responsible for tumor radioresistance. Methods: For TRT, we used a melanin radiotracer ([131I]ICF01012) currently in phase 1 clinical trial (NCT03784625). TRT alone or combined with MEKi was evaluated in three-dimensional melanoma spheroid models of human BRAFV600E SK-MEL-3, murine NRASQ61K 1007, and WT B16F10 melanomas. TRT in vivo biodistribution, dosimetry, efficiency, and molecular mechanisms were studied using the C57BL/6J-NRASQ61K 1007 syngeneic model. Results: TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant spheroids. NRASQ61K spheroids were highly radiosensitive towards [131I]ICF01012-TRT. In mice bearing NRASQ61K 1007 melanoma, [131I]ICF01012 induced a significant extended survival (92 vs. 44 days, p < 0.0001), associated with a 93-Gy tumor deposit, and reduced lymph-node metastases. Comparative transcriptomic analyses confirmed a decrease in mitosis, proliferation, and metastasis signatures in TRT-treated vs. control tumors and suggest that TRT acts through an increase in oxidation and inflammation and P53 activation. Conclusion: Our data suggest that [131I]ICF01012-TRT and MEKi combination could be of benefit for advanced pigmented BRAF-mutant melanoma care and that [131I]ICF01012 alone could constitute a new potential NRAS-mutant melanoma treatment.

Dataset Information

Inhibition of NRAS Signaling in Melanoma through Direct Depalmitoylation Using Amphiphilic Nucleophiles.

Publications

Inhibition of NRAS Signaling in Melanoma through Direct Depalmitoylation Using Amphiphilic Nucleophiles.

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