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

SIMPLE SUMMARY: NRAS-mutant melanoma is a highly aggressive subtype with few treatment options. Although both BRAF-mutant and NRAS-mutant melanomas have activation of the MEK/ERK pathway, MEK inhibitors (MEKi) are only effective for the BRAF-mutant subtype. The aim of this study was to understand why MEKi are ineffective in NRAS-mutant melanomas with the long-term goal of identifying new treatment regimens. Here, we show that ABL and DDR kinases are critically important for MEKi resistance because they cooperate to promote the stability of key proteins involved in driving melanoma growth and survival. FDA-approved drugs that inhibit ABL1/2 and DDR1 have been used for decades to treat leukemia. We showed that one such inhibitor prevents MEKi resistance from developing in a NRAS-mutant melanoma animal model. Thus, the data in this study provide the rationale for testing the use of drugs targeting ABL1/2 and DDR1 in combination with MEKi for patients with NRAS-mutant melanomas who have failed to respond to immunotherapy. 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.