| Autor: |
Lyon A; Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA., Tripathi R; Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA., Meeks C; Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA., He D; Biostatistics and Bioinformatics Shared Resource Facility, College of Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40508, USA., Wu Y; Biostatistics and Bioinformatics Shared Resource Facility, College of Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40508, USA., Liu J; Biostatistics and Bioinformatics Shared Resource Facility, College of Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40508, USA., Wang C; Biostatistics and Bioinformatics Shared Resource Facility, College of Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40508, USA., Chen J; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA., Zhu H; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA., Mukherjee S; Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA., Ganguly S; Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA., Plattner R; Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA. |
| Abstrakt: |
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. |
