Combating Acquired Resistance to MAPK Inhibitors in Melanoma by Targeting Abl1/2-Mediated Reactivation of MEK/ERK/MYC Signaling
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.
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This work was supported by the Markey Cancer Center Biospecimen and Tissue Procurement, Flow Cytometry, Oncogenomics, and Biostatistics and Bioinformatics Shared Resources, as well as the Research Communication Office (P30CA177558).
Next-generation sequencing (WES) data have been deposited in the NCBI/SRA database under the accession code (PRJNA639552). Links to data analyzed from the GEO database (accession #s 50509, 5077940, 50535, 65185), Genomic Data Commons (GDC), and link to the official database housing EGAS1000992 (data kindly provided by Dr. Lawrence Kwong; MD Anderson, TX; European Genome-phenome Archive) are below. https://portal.gdc.cancer.gov/projects/TCGA-SKCM; https://www.ebi.ac.uk/ega/datasets.
Tripathi, Rakshamani; Liu, Zulong; Jain, Aditi; Lyon, Anastasia; Meeks, Christina; Richards, Dana; Liu, Jinpeng; He, Daheng; Wang, Chi; Nespi, Marika; Rymar, Andrey; Wang, Peng; Wilson, Melissa; and Plattner, Rina, "Combating Acquired Resistance to MAPK Inhibitors in Melanoma by Targeting Abl1/2-Mediated Reactivation of MEK/ERK/MYC Signaling" (2020). Pharmacology and Nutritional Sciences Faculty Publications. 106.
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Published in Nature Communications, v. 11, issue 1, 5463.
© The Author(s) 2020
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