Combating Acquired Resistance to MAPK Inhibitors in Melanoma by Targeting Abl1/2-Mediated Reactivation of MEK/ERK/MYC Signaling

Authors

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

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.

Document Type

Article

Publication Date

10-29-2020

Notes/Citation Information

Published in Nature Communications, v. 11, issue 1, 5463.

© The Author(s) 2020

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.

Digital Object Identifier (DOI)

https://doi.org/10.1038/s41467-020-19075-3

Funding Information

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).

Related Content

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.

Repository Citation

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.
https://uknowledge.uky.edu/pharmacol_facpub/106