Abstract
Melanomas harboring NRAS mutations are a particularly aggressive and deadly subtype. If patients cannot tolerate or the melanomas are insensitive to immune checkpoint blockade, there are no effective 2nd-line treatment options. Drugs targeting the RAF/MEK/ERK pathway, which are used for BRAF-mutant melanomas, do little to increase progression-free survival (PFS). Here, using both loss-of-function and gain-of-function approaches, we show that ABL1/2 and DDR1 are critical nodes during NRAS-mutant melanoma intrinsic and acquired MEK inhibitor (MEKi) resistance. In some acquired resistance cells, ABL1/2 and DDR1 cooperate to stabilize RAF proteins, activate ERK cytoplasmic and nuclear signaling, repress p27/KIP1 expression, and drive RAF homodimerization. In contrast, other acquired resistance cells depend solely on ABL1/2 for their survival, and are sensitive to highly specific allosteric ABL1/2 inhibitors, which prevent β-catenin nuclear localization and destabilize MYC and ETS1 in an ERK-independent manner. Significantly, targeting ABL1/2 and DDR1 with an FDA-approved anti-leukemic drug, reverses intrinsic MEKi resistance, delays acquisition of acquired resistance, and doubles the survival time in a NRAS-mutant mouse model. These data indicate that repurposing FDA-approved drugs targeting ABL1/2 and DDR1 may be a novel and effective strategy for treating patients with treatment-refractory NRAS-driven melanomas.
Document Type
Article
Publication Date
2-2023
Digital Object Identifier (DOI)
https://doi.org/10.3390/cancers15030954
Funding Information
This research was funded by the following grants to the R.P. Lloyd Charitable Trust; The University of Kentucky Markey Cancer Foundation Women’s Strong Award; National Institute of Health Cancer Center Support Grant Pilot Award (5P30CA177558); NIH/NCI R01CA211137; and Kentuckiana Friends of the V Foundation Award.
Repository Citation
Lyon, Anastasia; Tripathi, Rakshamani; Meeks, Christina; He, Daheng; Wu, Yuanyuan; Liu, Jinpeng; Wang, Chi; Chen, Jing; Zhu, Haining; Mukherjee, Sujata; Ganguly, Saptadwipa; and Plattner, Rina, "ABL1/2 and DDR1 Drive MEKi Resistance in NRAS-Mutant Melanomas by Stabilizing RAF/MYC/ETS1 and Promoting RAF Homodimerization" (2023). Markey Cancer Center Faculty Publications. 281.
https://uknowledge.uky.edu/markey_facpub/281
Notes/Citation Information
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).