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Resistance mechanisms to genetic suppression of mutant NRAS in melanoma

James P Robinson1, Vito W Rebecca, David A Kircher

  • 1aThe Hormel Institute, University of Minnesota, Austin, Minnesota bDepartment of Medicine and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Departments of cOncological Sciences dSurgery eDermatology fHuntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah gDepartment of Tumor Biology, Tumor Biology hDepartment of Cutaneous Oncology, Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida iDepartment of Medicine, Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital jDepartment of Global Health, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, DC kDepartment of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Melanoma Research
|October 28, 2017
PubMed

Insights

Targeted therapies for NRAS-mutant melanoma can lead to resistance. Combining receptor tyrosine kinase (RTK) and mitogen-activated protein kinase kinase (MEK) inhibition can overcome this resistance, offering new treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Targeted therapies have transformed cancer treatment, but drug resistance is a significant clinical hurdle.
  • NRAS mutations are common drivers in melanoma, and therapies targeting this pathway are under development.
  • Understanding resistance mechanisms is crucial for designing effective combination therapies.

Purpose of the Study:

  • To investigate mechanisms of resistance to NRAS targeted therapy in melanoma.
  • To identify rational combination strategies to overcome treatment resistance.
  • To evaluate the therapeutic potential of combined RAS and receptor tyrosine kinase (RTK) inhibition.

Main Methods:

  • Utilized a genetically engineered mouse model of melanoma with NRAS suppression.
  • Selected for tumors resistant to NRAS inhibition.
  • Analyzed resistant tumors for molecular alterations, focusing on RTK signaling.
  • Assessed the efficacy of Met inhibition and combined RTK/MEK inhibition in vitro and in vivo.

Main Results:

  • Complete tumor regression was observed initially, but 40% of tumors recurred due to resistance.
  • Overexpression and activation of RTKs, particularly Met, was the predominant resistance mechanism.
  • Inhibition of Met effectively overcame NRAS resistance in the mouse model.
  • Combined RTK and mitogen-activated protein kinase kinase (MEK) inhibition enhanced cytotoxicity in NRAS-mutant human melanoma cells.

Conclusions:

  • Adaptive RTK signaling is a key mechanism by which NRAS-mutant melanoma escapes RAS inhibition.
  • Combined blockade of RAS and RTK signaling presents a promising therapeutic strategy for NRAS-mutant melanoma.
  • Targeting Met and other RTKs alongside MEK inhibitors could improve treatment outcomes.

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