Identified a mechanism for resistance in melanoma
[Adapted from Cancer Res]
20 Dec 2017
Identified a mechanism for resistance in melanoma

Although melanoma only accounts for less than 5% of skin cancers, it is nevertheless responsible for 80% of deaths from skin cancers. The BRAF V600E mutation is the most prevalent genetic alteration in malignant melanoma, and the target of the BRAF inhibitors (BRAFi), vemurafenib (VMF) and dabrafenib. Both therapeutic agents have provided substantial benefits for melanoma patients, but still a major challenge in melanoma treatment with mitogen-activated protein kinase (MAPK)-targeted therapy is an almost universal emergence of resistance that leads to disease relapse. Although the most frequent mechanisms involved in BRAFi resistance of melanoma cells converge in the reactivation of the MAPK pathway, a significant portion of tumors (40%) displays unknown resistance mechanisms that cannot be accounted for genetic alterations.   

The article published in Cancer Research by the group of Dr. Joaquin Teixidó at the Centro de Investigaciones Biológicas, has focused on the class of small non-coding RNAs called microRNAs (miRNAs) that have emerged as key post-transcriptional regulators in tumor progression. The experimental work included a 3-month visit of Marta Díaz Martínez, first author of the manuscript, in the laboratory of Dr. Eva Hernando, at the New York University School of Medicine. Dr. Hernando is an internationally-recognized expert in melanoma and miRNA research, and has significantly contributed to the progression of the study.

The group of Dr. Teixidó performed RNA-seq analyses comparing miRNA expression in parental and VMF-resistant melanoma cells, and identified and characterized selected miRNAs which contribute to BRAFi resistance. This part of the study included work by Dr. Lola Alonso from the Bioinformatics and Biostatistics Unit at CIB. Thus, increased expression of miR-204-5p and miR-211-5p occurring in VMF-resistant melanoma cells was determined to impact VMF response. Importantly, ectopic expression of both miRNA in drug-naive human melanoma cells was sufficient to confer VMF resistance and more robust tumor growth in vivo. Conversely, silencing their expression in resistant cells inhibited cell growth. Joint overexpression of miR-204-5p and miR-211-5p durably stimulated Ras and MAPK upregulation after VMF exposure.

Overall, these findings show how early upregulation of miR-204-5p and miR-211-5p following VMF treatment enables the emergence of resistance in melanoma, with potential implications for mechanism-based strategies to improve VMF responses.

Reference: miR-204-5p and miR-211-5p contribute to BRAF inhibitor resistance in melanoma. Marta Díaz-Martínez, Lucía Benito-Jardón, Lola Alonso, Lisa Koetz-Ploch, Eva Hernando, Joaquín Teixidó. Cancer Res (2017), Dec 11. doi: 10.1158/0008-5472.CAN-17-1318.