Combating acquired resistance to MAPK inhibitors in melanoma by targeting Abl1/2-mediated reactivation of MEK/ERK/MYC signaling

• Published in: Nature communications Vol. 11; no. 1; pp. 5463 - 18
• Main Authors: 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, Plattner, Rina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29-10-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/89; 38/23; 631/67/1059/2326; 631/67/1813/1634; 631/80/86; 692/699/67/395; 82/1; 82/29; 82/51; 96/106; 96/95; Cell Line, Tumor; Drug Resistance, Neoplasm - genetics; Enzyme inhibitors; Extracellular signal-regulated kinase; Humanities and Social Sciences; Humans; Immunotherapy; Inhibitors; Kinases; Leukemia; MAP kinase; MAP Kinase Signaling System - drug effects; MEK inhibitors; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Metastases; Metastasis; Mitogen-Activated Protein Kinase Kinases - drug effects; Mitogen-Activated Protein Kinase Kinases - metabolism; multidisciplinary; Mutants; Mutation; Mutation - drug effects; Myc protein; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-abl - genetics; Proto-Oncogene Proteins c-abl - metabolism; Pyrimidines - pharmacology; Science; Science (multidisciplinary); Signaling; Survival; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19075-3

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 (2
nd
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.