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

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. To understand how [131I]ICF01012 disrupts melanoma growth, 1007 NRAS mouse melanoma cells (1.10e5) were injected subacutaneously in the right flank of 5 weeks old C57BL/6J mice. 36 days after cell injection, a single administration of either 18.5 MBq/100 µL of [131I]ICF01012 (n=3) or with 100 µL of saline (n=6) was given intravenously to the mice. Tumors were harvested 10 days after treatment and snap-frozed in liquid nitrogen. Total RNA was extracted and sequenced (RNA-seq).The results confirm that [131I]ICF01012 inhibits cell growth and suggest different mechanism of action : 1) through oxydation, 2) linked with p53 activation and 3) via an immune response.