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.
|State||Published - Dec 1 2020|
Bibliographical noteFunding Information:
This research is/was funded by the following grants to R.P.: National Institute of Health (NCI): R01 CA211137 and R01 CA166499; Lloyd Charitable Trust; University of Kentucky Markey Foundation Women’s Strong Award; and Cancer Center Support Grant Pilot Award (5P30CA177558). M.N. and A.R. are employees of Plexxikon Inc.; all other authors declare no competing interests.
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). We thank Dr. Lawrence Kwong (MD Anderson) for EGAS RNAseq data; Novartis for supplying nilotinib and dabrafenib; Plexxikon Inc. for supplying PLX4720; Dr. Meenhard Herlyn (Wistar Institute) for supplying 451-Lu, Mel1617, and WM164 cell lines; and Drs. Qing-Bai She and Vivek Rangnekar (University of Kentucky) for critically reading the manuscript.
© 2020, The Author(s).
ASJC Scopus subject areas
- Chemistry (all)
- Biochemistry, Genetics and Molecular Biology (all)
- Physics and Astronomy (all)