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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• NRAS-mutant melanomas are aggressive with limited treatment options after immune checkpoint blockade failure.
• Current MEK inhibitors (MEKi) show limited efficacy in NRAS-mutant melanoma, especially upon acquired resistance.

Purpose of the Study:

• To identify critical molecular targets driving intrinsic and acquired MEK inhibitor resistance in NRAS-mutant melanoma.
• To evaluate the therapeutic potential of targeting identified nodes, including repurposing FDA-approved drugs.

Main Methods:

• Utilized loss-of-function and gain-of-function genetic approaches to investigate NRAS-mutant melanoma resistance mechanisms.
• Employed an FDA-approved anti-leukemic drug targeting ABL1/2 and DDR1 in preclinical models.

Main Results:

• Identified ABL1/2 and DDR1 as key regulators of MEK inhibitor resistance in NRAS-mutant melanoma.
• Demonstrated that ABL1/2 and DDR1 cooperate to stabilize RAF proteins and activate ERK signaling in some resistant cells.
• Showed that targeting ABL1/2 with specific inhibitors can overcome resistance independently of ERK signaling.
• Repurposing an FDA-approved drug targeting ABL1/2 and DDR1 reversed intrinsic resistance, delayed acquired resistance, and doubled survival in a mouse model.

Conclusions:

• ABL1/2 and DDR1 are critical therapeutic targets for overcoming MEK inhibitor resistance in NRAS-mutant melanoma.
• Repurposing FDA-approved drugs targeting ABL1/2 and DDR1 presents a promising novel strategy for treatment-refractory NRAS-driven melanomas.