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Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric

Fuyang Li1, Kathryn M Bondra1, Samson Ghilu1

  • 1Greehey Children's Cancer Research Institute, UT Health, San Antonio, Texas.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 7, 2022
PubMed
Abstract

Insights

Trametinib effectively treats pediatric BRAF-mutant brain tumors by inhibiting MAPK and TORC1 signaling. Combining trametinib with rapamycin prevents or delays acquired resistance, offering a promising therapeutic strategy for gliomas.

Area of Science:

  • Pediatric oncology
  • Molecular biology
  • Cancer therapeutics

Background:

  • BRAFV600E mutations drive aggressive pediatric brain tumors.
  • Low-grade gliomas (LGG) are a significant challenge in pediatric neuro-oncology.
  • Targeting the MAPK pathway is a key strategy for BRAF-mutant gliomas.

Purpose of the Study:

  • Investigate trametinib sensitivity in pediatric BRAFV600E-mutant brain tumor models.
  • Examine mechanisms of acquired trametinib resistance.
  • Evaluate strategies to prevent or overcome resistance, potentially for LGG.

Main Methods:

  • Utilized three patient-derived xenograft (PDX) models of pediatric BRAFV600E-mutant brain tumors.
  • Assessed sensitivity to trametinib (MEK inhibitor) alone and with rapamycin (TORC1 inhibitor).
  • Characterized PDX tissues and cells from resistant xenografts to understand resistance mechanisms.

Main Results:

  • Trametinib induced tumor regression via dual inhibition of MAPK and TORC1 signaling.
  • Acquired resistance to trametinib developed rapidly (within three cycles) in all models.
  • Resistance mechanisms were tumor-line specific and intrinsic to tumor cells.
  • Rapamycin significantly retarded or blocked the development of trametinib resistance.

Conclusions:

  • TORC1 signaling is MAPK-dependently activated in these pediatric brain tumors.
  • Combined trametinib and rapamycin therapy prevents or delays resistance development.
  • This combination strategy holds therapeutic potential for KIAA1549::BRAF- and BRAFV600E-driven gliomas.

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