Identification of new therapies for the treatment of BRAF/NRAS wild-type melanomas by functional screening approaches

Marco Ranzani, Magali Michaut, Clara Alsinet, Vera Grinkevich, Kim Wong, Vivek Iyer, Nanne Aben, Martin Del Castillo Velasco-Herrera, Marcela Sjoberg, Mamunur Rashid, Graham Bignell, Ken Dutton-Regester, Antonia Pritchard, Daniel Vis, Gemma Turner, Ultan McDermott, Nicholas K. Hayward, Kosuke Yusa, Lodewyk Wessels, Mathew GarnettDavid Adams

Research output: Contribution to journalArticlepeer-review


Melanoma causes 9000 deaths each year in the USA alone, more than one every hour. It represents the common tumor whose incidence has increased the most in the last 30 years. Despite promising advances, including immunotherapies, the therapeutic regimens are curative in only a fraction of patients. Implementation and combination of different therapeutic modalities is therefore required to improve patient survival.

Given the clinical efficacy of drug combinations for BRAF mutant melanomas, we performed a high-throughput drug screening to identify new drug combinations for the treatment of BRAF/NRAS wild type melanomas. Effective targeted therapies are not currently available for this sub-type of the disease, which represents up to 30% of melanomas. By viability assays we characterized the sensitivity to 240 combinations of clinically relevant drugs in a collection of 21 BRAF/NRAS wild type melanoma cell lines. We analysed 8360 survival curves and found that 16 (73%) and 5 (23%) cell lines are highly sensitive to temozolomide plus olaparib and to nilotinib plus trametinib combinations, respectively. Two independent experimental approaches validated these drug synergies.

By -omics technologies we deeply characterized the cell line profiles of mutations, copy number changes, DNA methylation, and gene and microRNA expression. We generated gene expression signatures of synergistic and resistant cell lines for the 2 drug combinations and used them to classify 374 human melanomas. Tumors significantly associated to nilotinib plus trametinib synergism signature were significantly enriched for high immune response and proliferative Jonsson's expression classes, while tumors associated to the signature of drug resistance are enriched for pigmentation class. Melanomas associated to temozolomide plus olaparib resistance signature displayed enrichment for normal class. We are currently confirming the representation of these signatures in an independent cohort of melanomas and looking for other clinical correlates. We are also validating the predictivity of these gene expression signatures in independent cohorts of melanoma cell lines. Prospectively, this may represent an approach to identify patients that could have the maximal benefit from these drug combinations.

Additionally, we have recently performed a genome-wide CRISPR/Cas9 screen to identify drug resistance genes for these 2 drug combinations. Preliminary results indicate a prominent role of tuberous sclerosis complex in the regulation of the sensitivity to nilotinib plus trametinib combination.

These results may pave the way to the development of novel patient-tailored targeted therapies for the efficient eradication of BRAF/NRAS wild type melanomas.
Original languageEnglish
Article numberpp 4783
JournalCancer Research
Issue number14
Publication statusPublished - Jul 2016


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