Related Experiment Video

Updated: Nov 26, 2025

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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SPRED1 deletion confers resistance to MAPK inhibition in melanoma

Julien Ablain1, Sixue Liu2,3, Gatien Moriceau2,3,4

  • 1Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA.

The Journal of Experimental Medicine
|December 11, 2020
PubMed

Insights

SPRED1 loss promotes melanoma resistance to BRAF inhibitors by reactivating MAPK signaling. This discovery in human cells and zebrafish offers new therapeutic strategies for BRAF-mutant melanoma.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • SPRED1 is a negative regulator of the MAPK pathway.
  • SPRED1 was previously identified as a tumor suppressor in KIT-driven melanoma.
  • BRAF mutations are common drivers in melanoma, and MAPK pathway inhibitors are key therapies.

Purpose of the Study:

  • To investigate the role of SPRED1 in BRAF-mutant melanoma.
  • To determine if SPRED1 inactivation contributes to resistance against BRAFV600E inhibitors.
  • To elucidate the mechanism by which SPRED1 loss affects melanoma progression under BRAF inhibition.

Main Methods:

  • Analysis of SPRED1 deletion frequency in human melanoma.
  • In vitro studies using human melanoma cell lines.
  • In vivo studies using a zebrafish melanoma model.
  • Assessment of MAPK pathway activity and cell proliferation.

Main Results:

  • SPRED1 is frequently deleted in BRAF-mutant melanoma.
  • SPRED1 inactivation confers resistance to BRAFV600E inhibition in vitro and in vivo.
  • Loss of SPRED1 reactivates MAPK signaling, promoting proliferation under BRAF inhibition.
  • A patient with acquired resistance to MAPK-targeted therapy showed biallelic SPRED1 deletion.

Conclusions:

  • SPRED1 functions as a tumor suppressor in BRAF-mutant melanoma.
  • SPRED1 loss is a novel mechanism of resistance to BRAFV600E inhibitors.
  • Targeting SPRED1 or understanding its role may overcome therapeutic resistance in melanoma.

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