Akil Hussein, Quintana Mercedes, Raymond Jérémy H, Billoux Tommy, Benboubker Valentin, Besse Sophie, Auzeloux Philippe, Delmas Véronique, Petit Valérie, Larue Lionel, D'Incan Michel, Degoul Françoise, Rouanet Jacques
INSERM U1240, University of Clermont Auvergne, 58 rue Montalembert, 63000 Clermont-Ferrand, France.
CNRS 7276, INSERM U1262, 2 rue du Pr Descottes, 87025 Limoges, France.
Cancers (Basel). 2021 Mar 20;13(6):1421. doi: 10.3390/cancers13061421.
To assess the efficiency of targeted radionuclide therapy (TRT), alone or in combination with MEK inhibitors (MEKi), in melanomas harboring constitutive MAPK/ERK activation responsible for tumor radioresistance.
For TRT, we used a melanin radiotracer ([I]ICF01012) currently in phase 1 clinical trial (NCT03784625). TRT alone or combined with MEKi was evaluated in three-dimensional melanoma spheroid models of human BRAF SK-MEL-3, murine NRAS 1007, and WT B16F10 melanomas. TRT in vivo biodistribution, dosimetry, efficiency, and molecular mechanisms were studied using the C57BL/6J-NRAS 1007 syngeneic model.
TRT cooperated with MEKi to increase apoptosis in both BRAF- and NRAS-mutant spheroids. NRAS spheroids were highly radiosensitive towards [I]ICF01012-TRT. In mice bearing NRAS 1007 melanoma, [I]ICF01012 induced a significant extended survival (92 vs. 44 days, < 0.0001), associated with a 93-Gy tumor deposit, and reduced lymph-node metastases. Comparative transcriptomic analyses confirmed a decrease in mitosis, proliferation, and metastasis signatures in TRT-treated vs. control tumors and suggest that TRT acts through an increase in oxidation and inflammation and P53 activation.
Our data suggest that [I]ICF01012-TRT and MEKi combination could be of benefit for advanced pigmented BRAF-mutant melanoma care and that [I]ICF01012 alone could constitute a new potential NRAS-mutant melanoma treatment.
评估靶向放射性核素治疗（TRT）单独或与MEK抑制剂（MEKi）联合使用，在因组成型MAPK/ERK激活导致肿瘤放射抗性的黑色素瘤中的疗效。
对于TRT，我们使用了一种目前处于1期临床试验（NCT03784625）的黑色素放射性示踪剂（[I]ICF01012）。在人BRAF SK-MEL-3、小鼠NRAS 1007和野生型B16F10黑色素瘤的三维黑色素瘤球体模型中评估单独的TRT或与MEKi联合使用的情况。使用C57BL/6J-NRAS 1007同基因模型研究TRT的体内生物分布、剂量测定、疗效和分子机制。
TRT与MEKi协同作用，增加BRAF和NRAS突变球体中的细胞凋亡。NRAS球体对[I]ICF01012-TRT高度放射敏感。在携带NRAS 1007黑色素瘤的小鼠中，[I]ICF01012显著延长了生存期（92天对44天，<0.0001），与93 Gy的肿瘤沉积相关，并减少了淋巴结转移。比较转录组分析证实，与对照肿瘤相比，TRT治疗的肿瘤中，有丝分裂、增殖和转移特征减少，并表明TRT通过氧化、炎症增加和P53激活发挥作用。
我们的数据表明，[I]ICF01012-TRT与MEKi联合使用可能对晚期BRAF突变的色素性黑色素瘤治疗有益，且单独使用[I]ICF01012可能构成NRAS突变黑色素瘤的一种新的潜在治疗方法。
