Dataset Information

Variation of mutant allele frequency in NRAS Q61 mutated melanomas.

ABSTRACT: BACKGROUNDSomatic mutations of BRAF or NRAS activating the MAP kinase cell signaling pathway are present in 70% of cutaneous melanomas. The mutant allele frequency of BRAF V600E (M%BRAF) was recently shown to be highly heterogeneous in melanomas. The present study focuses on the NRAS Q61 mutant allele frequency (M%NRAS).METHODSRetrospective quantitative analyze of 104 NRAS mutated melanomas was performed using pyrosequencing. Mechanisms of M%NRAS imbalance were studied by fluorescence in situ hybridization (FISH) and microsatellite analysis.RESULTSM%NRAS was increased in 27.9% of cases. FISH revealed that chromosome 1 instability was the predominant mechanism of M%NRAS increase, with chromosome 1 polysomy observed in 28.6% of cases and intra-tumor cellular heterogeneity with copy number variations of chromosome 1/NRAS in 23.8%. Acquired copy-neutral loss of heterozygosity (LOH) was less frequent (19%). However, most samples with high M%NRAS had only one copy of NRAS locus surrounding regions suggesting a WT allele loss. Clinical characteristics and survival of patients with either <60% or ?60% of M%NRAS were not different.CONCLUSIONAs recently shown for M%BRAF, M%NRAS is highly heterogeneous. The clinical impacts of high M%NRAS should be investigated in a larger series of patients.

SUBMITTER: Helias-Rodzewicz Z

PROVIDER: S-EPMC5494128 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Variation of mutant allele frequency in NRAS Q61 mutated melanomas.

Hélias-Rodzewicz Zofia Z Funck-Brentano Elisa E Terrones Nathalie N Beauchet Alain A Zimmermann Ute U Marin Cristi C Saiag Philippe P Emile Jean-François JF

BMC dermatology 20170701 1

<h4>Background</h4>Somatic mutations of BRAF or NRAS activating the MAP kinase cell signaling pathway are present in 70% of cutaneous melanomas. The mutant allele frequency of BRAF V600E (M%BRAF) was recently shown to be highly heterogeneous in melanomas. The present study focuses on the NRAS Q61 mutant allele frequency (M%NRAS).<h4>Methods</h4>Retrospective quantitative analyze of 104 NRAS mutated melanomas was performed using pyrosequencing. Mechanisms of M%NRAS imbalance were studied by fluor ...[more]

PMID: 28668077

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Project description:Simple Summary NRAS-mutant melanoma is a highly aggressive subtype with few treatment options. Although both BRAF-mutant and NRAS-mutant melanomas have activation of the MEK/ERK pathway, MEK inhibitors (MEKi) are only effective for the BRAF-mutant subtype. The aim of this study was to understand why MEKi are ineffective in NRAS-mutant melanomas with the long-term goal of identifying new treatment regimens. Here, we show that ABL and DDR kinases are critically important for MEKi resistance because they cooperate to promote the stability of key proteins involved in driving melanoma growth and survival. FDA-approved drugs that inhibit ABL1/2 and DDR1 have been used for decades to treat leukemia. We showed that one such inhibitor prevents MEKi resistance from developing in a NRAS-mutant melanoma animal model. Thus, the data in this study provide the rationale for testing the use of drugs targeting ABL1/2 and DDR1 in combination with MEKi for patients with NRAS-mutant melanomas who have failed to respond to immunotherapy. Abstract Melanomas harboring NRAS mutations are a particularly aggressive and deadly subtype. If patients cannot tolerate or the melanomas are insensitive to immune checkpoint blockade, there are no effective 2nd-line treatment options. Drugs targeting the RAF/MEK/ERK pathway, which are used for BRAF-mutant melanomas, do little to increase progression-free survival (PFS). Here, using both loss-of-function and gain-of-function approaches, we show that ABL1/2 and DDR1 are critical nodes during NRAS-mutant melanoma intrinsic and acquired MEK inhibitor (MEKi) resistance. In some acquired resistance cells, ABL1/2 and DDR1 cooperate to stabilize RAF proteins, activate ERK cytoplasmic and nuclear signaling, repress p27/KIP1 expression, and drive RAF homodimerization. In contrast, other acquired resistance cells depend solely on ABL1/2 for their survival, and are sensitive to highly specific allosteric ABL1/2 inhibitors, which prevent β-catenin nuclear localization and destabilize MYC and ETS1 in an ERK-independent manner. Significantly, targeting ABL1/2 and DDR1 with an FDA-approved anti-leukemic drug, reverses intrinsic MEKi resistance, delays acquisition of acquired resistance, and doubles the survival time in a NRAS-mutant mouse model. These data indicate that repurposing FDA-approved drugs targeting ABL1/2 and DDR1 may be a novel and effective strategy for treating patients with treatment-refractory NRAS-driven melanomas.

Dataset Information

Variation of mutant allele frequency in NRAS Q61 mutated melanomas.

Publications

Variation of mutant allele frequency in NRAS Q61 mutated melanomas.

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