Melanoma is the most common lethal form of skin cancer. Activating mutations in BRAF and RAS oncogenes account for over 80% of all melanomas and hyper-activate the MAPK cascade. Despite major advances in targeted melanoma therapies over the past decade, drug resistance limits their efficacy.

Long noncoding RNAs (lncRNAs) are a new class of genes that do not encode proteins, which have been characterized as epigenetic regulatory molecules. LncRNAs have emerged as important players in cancer, potential predictors of therapeutic responses and targets for new treatments; however, their functions and precise molecular mechanisms remains largely unexplored.

Our study aims to find novel potential targets involved in the acquisition of resistance to MAPK inhibitors.

We identified an intergenic lncRNA (lincRNA) highly differentially expressed in drug-resistant melanoma samples, called MAPK Inhibitor Resistance Associated Transcript (MIRAT). We determined that MIRAT is localized mainly in the cytoplasm and plays a role in modulating the signal transduction pathways without regulating the genomic neighborhood. We discovered that MIRAT is upregulated in early drug tolerance to MAPK inhibition. Mechanistically, the gene overexpression and silencing of MIRAT, as well as preliminary RNA-protein interaction results, showed that it modulates the MAPK signal transduction pathway by binding to a downstream target of MEK.

Collectively, these results highlight the relevance of cytoplasmic lincRNA’s and their role in oncogenic signaling pathways, and further suggest that lncRNAs and their protein-binding partners may serve as novel potential targets for overcoming drug resistance in melanoma.

Note: This abstract was not presented at the meeting.

Citation Format: Rosaura Esteve-Puig, Martina Sanlorenzo, Igor Vujic, Kevin Lai, Marin Vujic, Dallas Mould, Kevin Lin, Juan Oses-Prieto, Shreya Chand, Christian Posch, Alma Burlingame, Susana Ortiz-Urda. LncRNA as potential target in drug-resistant melanomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3493. doi:10.1158/1538-7445.AM2017-3493