ABL1/2 and DDR1 Drive MEKi Resistance in NRAS-Mutant Melanomas by Stabilizing RAF/MYC/ETS1 and Promoting RAF Homodimerization

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.

Evidence That DDR1 Promotes Oligodendrocyte Differentiation during Development and Myelin Repair after Injury

“…A more recently identified negative regulators of oligodendrocyte differentiation is the MAPK/ERK pathway [ 27 , 45 , 46 , 47 ]. It was previously demonstrated that Ddr1 could modulate the activity of the AKT/ERK pathway and plays an important role in the migration and adhesion of cancer cells [ 30 , 48 , 49 ]. The Western blot analysis confirmed that inhibition of Ddr1 upregulates the ratio of p-ERK to total ERK without altering the AKT signaling pathway ( Figure 7 ).…”

Role and Function of Receptor Tyrosine Kinases in BRAF Mutant Cancers

“…Imatinib also augmented vemurafenib anticancer activity against BRAF V600E melanoma xenografts by suppressing collagen remodeling [327]. It was also shown that the acquired resistance of NRAS mutant melanomas to trametinib was mediated by DDR1 activation [328]. DDR1 and DDR2 were overexpressed together with ephedrine receptors in double vemurafenib-and MEK inhibitor-cobimetinib-resistant BRAF V600E melanoma.…”