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NR2F1 and mTORC1 provide the bridge between melanoma dormancy and therapeutic resistance

Narsimha Mamidi1,2, Swadesh K Das1,2,3, Paul B Fisher1,2,3

  • 1Department of Cellular, Molecular and Genetic Medicine.

The Journal of Clinical Investigation
|September 16, 2025
PubMed

Insights

Drug-tolerant melanoma cells resist treatment by activating NR2F1. Combining BRAF/MEK inhibitors with rapamycin targets these cells, offering a new strategy for cutaneous melanoma patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • Cutaneous melanoma (CM) exhibits aggressive behavior and high metastatic potential, leading to poor prognosis.
  • BRAF mutations are prevalent in CM, and BRAF/MEK inhibitor (BRAFi + MEKi) therapy shows efficacy.
  • Therapeutic response durability is limited by drug-tolerant residual cells, causing relapse.

Purpose of the Study:

  • To investigate the role of NR2F1 in therapeutic resistance in melanoma.
  • To explore NR2F1's impact on melanoma proliferation, invasion, and therapeutic efficacy.
  • To evaluate combination therapies targeting NR2F1 and mTORC1 signaling.

Main Methods:

  • Analysis of transcriptomic datasets from patients with minimal residual disease.
  • Overexpression of NR2F1 in murine and human melanoma models.
  • Assessment of BRAFi + MEKi efficacy alone and in combination with rapamycin (mTORC1 inhibitor).

Main Results:

  • NR2F1 expression was elevated in minimal residual disease.
  • NR2F1 overexpression reduced therapeutic efficacy, suppressed proliferation and invasion, and sustained mTORC1 signaling.
  • Combination therapy of BRAFi + MEKi with rapamycin effectively targeted resistant melanoma cells.

Conclusions:

  • NR2F1 is a key determinant of therapeutic resistance in melanoma.
  • Targeting NR2F1 and mTORC1 signaling presents a potential therapeutic strategy for CM patients.
  • Combination therapy may overcome resistance mediated by NR2F1 and mTORC1.

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