Lyon Anastasia, Tripathi Rakshamani, Meeks Christina, He Daheng, Wu Yuanyuan, Liu Jinpeng, Wang Chi, Chen Jing, Zhu Haining, Mukherjee Sujata, Ganguly Saptadwipa, Plattner Rina
Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
Biostatistics and Bioinformatics Shared Resource Facility, College of Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40508, USA.
Cancers (Basel). 2023 Feb 2;15(3):954. doi: 10.3390/cancers15030954.
Melanomas harboring 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 -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 -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 -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.
携带NRAS突变的黑色素瘤是一种特别侵袭性和致命的亚型。如果患者无法耐受或黑色素瘤对免疫检查点阻断不敏感，则没有有效的二线治疗选择。用于NRAS突变型黑色素瘤的靶向RAF/MEK/ERK途径的药物对增加无进展生存期（PFS）作用甚微。在这里，我们使用功能丧失和功能获得方法表明，ABL1/2和DDR1是NRAS突变型黑色素瘤内在和获得性MEK抑制剂（MEKi）耐药过程中的关键节点。在一些获得性耐药细胞中，ABL1/2和DDR1协同作用以稳定RAF蛋白，激活ERK细胞质和核信号传导，抑制p27/KIP1表达，并驱动RAF同源二聚化。相比之下，其他获得性耐药细胞仅依赖ABL1/2存活，并且对高度特异性的变构ABL1/2抑制剂敏感，该抑制剂可阻止β-连环蛋白核定位并以ERK非依赖方式使MYC和ETS1不稳定。重要的是，用一种FDA批准的抗白血病药物靶向ABL1/2和DDR1可逆转内在的MEKi耐药性，延迟获得性耐药的发生，并使NRAS突变小鼠模型的存活时间加倍。这些数据表明，重新利用FDA批准的靶向ABL1/2和DDR1的药物可能是治疗难治性NRAS驱动的黑色素瘤患者的一种新颖且有效的策略。
