ABL1/2 and DDR1 Drive MEKi Resistance in NRAS-Mutant Melanomas by Stabilizing RAF/MYC/ETS1 and Promoting RAF Homodimerization
Melanomas harboring <i>NRAS</i> 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 us...
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| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/3/954 |
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| author | Anastasia Lyon Rakshamani Tripathi Christina Meeks Daheng He Yuanyuan Wu Jinpeng Liu Chi Wang Jing Chen Haining Zhu Sujata Mukherjee Saptadwipa Ganguly Rina Plattner |
| author_facet | Anastasia Lyon Rakshamani Tripathi Christina Meeks Daheng He Yuanyuan Wu Jinpeng Liu Chi Wang Jing Chen Haining Zhu Sujata Mukherjee Saptadwipa Ganguly Rina Plattner |
| author_sort | Anastasia Lyon |
| collection | DOAJ |
| description | Melanomas harboring <i>NRAS</i> 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 <i>BRAF</i>-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 <i>NRAS</i>-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 <i>NRAS</i>-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. |
| first_indexed | 2024-03-11T09:50:12Z |
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| id | doaj.art-871a5cfedfa548e3aaba0d81896b5572 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T09:50:12Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-871a5cfedfa548e3aaba0d81896b55722023-11-16T16:19:36ZengMDPI AGCancers2072-66942023-02-0115395410.3390/cancers15030954ABL1/2 and DDR1 Drive MEKi Resistance in NRAS-Mutant Melanomas by Stabilizing RAF/MYC/ETS1 and Promoting RAF HomodimerizationAnastasia Lyon0Rakshamani Tripathi1Christina Meeks2Daheng He3Yuanyuan Wu4Jinpeng Liu5Chi Wang6Jing Chen7Haining Zhu8Sujata Mukherjee9Saptadwipa Ganguly10Rina Plattner11Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USADepartment of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USADepartment of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USABiostatistics and Bioinformatics Shared Resource Facility, College of Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40508, USABiostatistics and Bioinformatics Shared Resource Facility, College of Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40508, USABiostatistics and Bioinformatics Shared Resource Facility, College of Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40508, USABiostatistics and Bioinformatics Shared Resource Facility, College of Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40508, USADepartment of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USADepartment of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USADepartment of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USADepartment of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USADepartment of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USAMelanomas harboring <i>NRAS</i> 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 <i>BRAF</i>-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 <i>NRAS</i>-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 <i>NRAS</i>-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.https://www.mdpi.com/2072-6694/15/3/954whole exome sequencingRNA sequencingmelanomaNRASDDR1ABL1 |
| spellingShingle | Anastasia Lyon Rakshamani Tripathi Christina Meeks Daheng He Yuanyuan Wu Jinpeng Liu Chi Wang Jing Chen Haining Zhu Sujata Mukherjee Saptadwipa Ganguly Rina Plattner ABL1/2 and DDR1 Drive MEKi Resistance in NRAS-Mutant Melanomas by Stabilizing RAF/MYC/ETS1 and Promoting RAF Homodimerization Cancers whole exome sequencing RNA sequencing melanoma NRAS DDR1 ABL1 |
| title | ABL1/2 and DDR1 Drive MEKi Resistance in NRAS-Mutant Melanomas by Stabilizing RAF/MYC/ETS1 and Promoting RAF Homodimerization |
| title_full | ABL1/2 and DDR1 Drive MEKi Resistance in NRAS-Mutant Melanomas by Stabilizing RAF/MYC/ETS1 and Promoting RAF Homodimerization |
| title_fullStr | ABL1/2 and DDR1 Drive MEKi Resistance in NRAS-Mutant Melanomas by Stabilizing RAF/MYC/ETS1 and Promoting RAF Homodimerization |
| title_full_unstemmed | ABL1/2 and DDR1 Drive MEKi Resistance in NRAS-Mutant Melanomas by Stabilizing RAF/MYC/ETS1 and Promoting RAF Homodimerization |
| title_short | ABL1/2 and DDR1 Drive MEKi Resistance in NRAS-Mutant Melanomas by Stabilizing RAF/MYC/ETS1 and Promoting RAF Homodimerization |
| title_sort | abl1 2 and ddr1 drive meki resistance in nras mutant melanomas by stabilizing raf myc ets1 and promoting raf homodimerization |
| topic | whole exome sequencing RNA sequencing melanoma NRAS DDR1 ABL1 |
| url | https://www.mdpi.com/2072-6694/15/3/954 |
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