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

Anastasia Lyon, Rakshamani Tripathi, Christina Meeks, Daheng He, Yuanyuan Wu, Jinpeng Liu, Chi Wang, Jing Chen, Haining Zhu, Sujata Mukherjee, Saptadwipa Ganguly, Rina Plattner

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number954
JournalCancers
Volume15
Issue number3
DOIs
StatePublished - Feb 2023
Externally publishedYes

Keywords

  • ABL1
  • ABL2
  • ARAF
  • BRAF
  • CRAF
  • DDR1
  • ETS1
  • MYC
  • NRAS
  • RNA sequencing
  • melanoma
  • p27/KIP1
  • whole exome sequencing
  • β-catenin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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