The therapeutically actionable long non-coding RNA ‘T-RECS’ is essential to cancer cells’ survival in NRAS/MAPK-driven melanoma

Author:

Feichtenschlager Valentin,Chen Linan,Zheng Yixuan James,Ho Wilson,Sanlorenzo Martina,Vujic Igor,Fewings Eleanor,Lee Albert,Chen Christopher,Callanan Ciara,Lin Kevin,Qu Tiange,Hohlova Dasha,Vujic Marin,Hwang Yeonjoo,Lai Kevin,Chen Stephanie,Nguyen Thuan,Muñoz Denise P,Kohwi Yoshinori,Posch Christian,Daud Adil,Rappersberger Klemens,Kohwi-Shigematsu Terumi,Coppé Jean-Philippe,Ortiz-Urda Susana

Abstract

AbstractFinding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.

Funder

Verein zur Förderung der Dermatologischen Forschung

Impact Melanoma

Outrun the Sun, Inc. 2019 National Melanoma Research Scholar Award

HDFCCC Laboratory for Cell Analysis Shared Resource Facility

Publisher

Springer Science and Business Media LLC

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