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Updated: Dec 21, 2025

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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Targeting PHGDH Upregulation Reduces Glutathione Levels and Resensitizes Resistant NRAS-Mutant Melanoma to MAPK

Mai Q Nguyen1, Jessica L F Teh1, Timothy J Purwin1

  • 1Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

The Journal of Investigative Dermatology
|May 12, 2020
PubMed

Insights

NRAS-mutant melanoma develops resistance to MEK inhibitors by altering metabolism. Targeting PHGDH, an enzyme in serine synthesis, alongside MEK inhibitors may overcome this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Activating NRAS mutations drive melanoma, leading to MAPK pathway activation.
  • MEK inhibitors (MEKi) show limited clinical efficacy due to acquired resistance.
  • Therapy-resistant models often lack physiological metabolic conditions.

Purpose of the Study:

  • To investigate metabolic rewiring in MEKi-resistant NRAS-mutant melanoma.
  • To identify novel therapeutic targets for overcoming MEKi resistance.

Main Methods:

  • Generated in vivo human NRAS-mutant melanoma xenografts resistant to the MEK inhibitor PD0325901.
  • Assessed cross-resistance to trametinib and analyzed signaling pathways.
  • Quantified serine synthesis pathway and PHGDH enzyme expression.
  • Evaluated the effect of PHGDH suppression in combination with MEKi treatment.

Main Results:

  • MEKi-resistant xenografts exhibited cross-resistance to trametinib and sustained ERK1/2 signaling.
  • Upregulation of the serine synthesis pathway and PHGDH was observed in resistant cells.
  • Combined MEKi and PHGDH inhibition reduced oxidative stress tolerance and proliferation.

Conclusions:

  • PHGDH is upregulated in MEKi-resistant NRAS-mutant melanoma.
  • Targeting PHGDH represents a potential strategy to overcome MEK inhibitor resistance in melanoma.

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