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Targeted radionuclide therapy for pigmented BRAF- and NRAS-mutated melanoma: [131I]ICF01012 efficacy and combination with MAPK/ERK pathway inhibitors

ABSTRACT: Purpose: Tumor radioresistance can be driven by ERK phosphorylation and its downstream targets. In this context, melanomas harboring constitutive MAPK/ERK activation have been considered for targeted radionuclide therapy (TRT) with a radiolabeled melanin tracer ([131I]ICF01012), alone or in combination with MEK inhibitors (MEKi). Experimental design: We used three dimensional (3D) melanoma spheroid models to evaluate the effects of TRT in combination with MEKi, in human BRAFV600E SK-MEL-3, NRASQ61K 1007 and WT B16F10 murine melanomas. TRT was assessed in vivo using the syngeneic model C57Bl5/NRAS 1007 for biodistribution, dosimetry, efficiency and molecular mechanisms. Results: In spheroids, TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant models that were resistant to TRT-induced apoptosis. However NRASQ61K spheroids were highly radiosensitive towards [131I]ICF01012-TRT. Actually, mice bearing NRAS1007 melanoma and receiving 18.5MBq of [131I]ICF01012 had a significant extended survival (median: 92 vs 44 days, p < 0.0001), associated with a 93 Gy tumor deposit, leading to a dramatic decrease of tumor growth. Furthermore, the number of lymph node metastases was reduced in mice receiving [131I]ICF01012. Comparative transcriptomic analyses confirm a decrease of mitosis, proliferation and metastasis signature in TRT-treated tumors vs control tumors. These analyses also suggest that in this NRAS-melanoma, TRT acts through an increase of oxidation and inflammation as well as P53 activation. Conclusions: Our data support the view that combining [131I]ICF01012-TRT with MEKi can be of benefit for the treatment of advanced pigmented BRAF-mutant melanoma. Likewise, [131I]ICF01012 alone can be considered as a new potential NRAS-mutant melanoma treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE162536 | GEO | 2021/03/31

REPOSITORIES: GEO

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Project description:Purpose: The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. Although spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers in selecting patients for immune therapy. Experimental Design: We performed unsupervised hierarchical clustering of global gene expression data from stage IV melanomas in 57 patients. For further characterization, we used immunohistochemistry of selected markers, genome-wide DNA copy number analysis, genetic and epigenetic analysis of the Q3 CDKN2A locus, and NRAS/BRAF mutation screening. Results: The analysis revealed four distinct subtypes with gene signatures characterized by expression of immune response, pigmentation differentiation, proliferation, or stromal composition genes. Although all subtypes harbored NRAS and BRAF mutations, there was a significant difference between subtypes (P < 0.01), with no BRAF/NRAS wild-type samples in the proliferative subtype. Additionally, the proliferative subtype was characterized by a high frequency of CDKN2A homozygous deletions (P < 0.01). We observed a different prognosis between the subtypes (P = 0.01), with a particularly poor survival for patients harboring tumors of the proliferative subtype compared with the others (P = 0.003). Importantly, the clinical relevance of the subtypes was validated in an independent cohort of 44 stage III and IV melanomas. Moreover, low expression of an a priori defined gene set associated with immune response signaling was significantly associated with poor outcome (P = 0.001). Conclusions: Our data reveal a biologically based taxonomy of malignant melanomas with prognostic effect and support an influence of the antitumoral immune response on outcome. Expression profiles of 57 lymphnode and subcutaneous melanoma metastases

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Targeted radionuclide therapy for pigmented BRAF- and NRAS-mutated melanoma: [131I]ICF01012 efficacy and combination with MAPK/ERK pathway inhibitors

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