Combating acquired resistance to MAPK inhibitors in melanoma by targeting Abl1/2-mediated reactivation of MEK/ERK/MYC signaling
| Autor: | Daheng He, Marika Nespi, Zulong Liu, Christina Meeks, Anastasia Lyon, Jinpeng Liu, Andrey Rymar, Peng Wang, Chi Wang, Rina Plattner, Melissa Wilson, Aditi Jain, Rakshamani Tripathi, Dana Richards |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway MAP Kinase Signaling System Science General Physics and Astronomy Drug resistance Mitogen-activated protein kinase kinase Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Cell Line Tumor hemic and lymphatic diseases medicine Humans Proto-Oncogene Proteins c-abl lcsh:Science Melanoma Protein Kinase Inhibitors neoplasms Mitogen-Activated Protein Kinase Kinases Multidisciplinary ABL business.industry Kinase MEK inhibitor Oncogenes General Chemistry Protein-Tyrosine Kinases medicine.disease digestive system diseases Cancer therapeutic resistance Pyrimidines 030104 developmental biology Nilotinib Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mutation Cancer research lcsh:Q business Cell signalling medicine.drug |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-18 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Metastatic melanoma remains an incurable disease for many patients due to the limited success of targeted and immunotherapies. BRAF and MEK inhibitors reduce metastatic burden for patients with melanomas harboring BRAF mutations; however, most eventually relapse due to acquired resistance. Here, we demonstrate that ABL1/2 kinase activities and/or expression are potentiated in cell lines and patient samples following resistance, and ABL1/2 drive BRAF and BRAF/MEK inhibitor resistance by inducing reactivation of MEK/ERK/MYC signaling. Silencing/inhibiting ABL1/2 blocks pathway reactivation, and resensitizes resistant cells to BRAF/MEK inhibitors, whereas expression of constitutively active ABL1/2 is sufficient to promote resistance. Significantly, nilotinib (2nd generation ABL1/2 inhibitor) reverses resistance, in vivo, causing prolonged regression of resistant tumors, and also, prevents BRAFi/MEKi resistance from developing in the first place. These data indicate that repurposing the FDA-approved leukemia drug, nilotinib, may be effective for prolonging survival for patients harboring BRAF-mutant melanomas. Resistance to BRAF/MEK inhibitors is a major impediment to long-term survival for patients with BRAF-mutant melanomas. Here, the authors show that ABL kinases drive resistance by promoting MEK/ERK reactivation and the FDA-approved ABL kinase inhibitor nilotinib prevents and overcomes resistance. |
| Databáze: | OpenAIRE |
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