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

Rakshamani Tripathi, Zulong Liu, Aditi Jain, Anastasia Lyon, Christina Meeks, Dana Richards, Jinpeng Liu, Daheng He, Chi Wang, Marika Nespi, Andrey Rymar, Peng Wang, Melissa Wilson and Rina Plattner ()
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Rakshamani Tripathi: University of Kentucky College of Medicine
Zulong Liu: University of Kentucky College of Medicine
Aditi Jain: University of Kentucky College of Medicine
Anastasia Lyon: University of Kentucky College of Medicine
Christina Meeks: University of Kentucky College of Medicine
Dana Richards: University of Kentucky College of Medicine
Jinpeng Liu: University of Kentucky College of Medicine
Daheng He: University of Kentucky College of Medicine
Chi Wang: University of Kentucky College of Medicine
Marika Nespi: Plexxikon Inc.
Andrey Rymar: Plexxikon Inc.
Peng Wang: College of Medicine
Melissa Wilson: Thomas Jefferson University
Rina Plattner: University of Kentucky College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19075-3

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