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

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

  • Nat Commun. 2020 Oct 29;11(1):5463. doi: 10.1038/s41467-020-19075-3.
Rakshamani Tripathi 1,  Zulong Liu 1,  Aditi Jain 1 2,  Anastasia Lyon 1,  Christina Meeks 1,  Dana Richards 3,  Jinpeng Liu 4,  Daheng He 4,  Chi Wang 4,  Marika Nespi 5,  Andrey Rymar 5,  Peng Wang 6,  Melissa Wilson 7,  Rina Plattner 8
Affiliations

Affiliations

  • 1 Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
  • 2 The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
  • 3 Department of Pathology, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
  • 4 Biostatistics and Bioinformatics Shared Resource Facility, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, 40536, USA.
  • 5 Plexxikon Inc., Berkeley, CA, 94710, USA.
  • 6 Department of Internal Medicine, University of Kentucky, College of Medicine, Lexington, KY, USA.
  • 7 Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
  • 8 Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, 40536, USA. rplat2@uky.edu.
PMID: 33122628 DOI: 10.1038/s41467-020-19075-3
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.

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