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FGF2 Induces Resistance to Nilotinib through MAPK Pathway Activation in KIT Mutated Melanoma

Pauline Tétu1,2, Julie Delyon1,2, Jocelyne André1,3

  • 1INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France.

Cancers
|April 30, 2020
PubMed

Insights

Fibroblast Growth Factor 2 (FGF2) drives resistance to KIT inhibitors in melanoma by suppressing BIM expression via MAPK pathway activation. Combining KIT inhibitors with MEK inhibitors overcomes this resistance, offering a promising clinical strategy for KIT-mutant melanoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • KIT is an oncogene in a subset of melanoma, and KIT inhibitors show ex vivo efficacy.
  • KIT-mutant melanoma tumors often exhibit de novo resistance or limited response duration to KIT inhibitors.

Purpose of the Study:

  • To investigate mechanisms of resistance to KIT inhibition in melanoma.
  • To identify potential therapeutic strategies to overcome resistance in KIT-mutant melanoma.

Main Methods:

  • Pharmacodynamic studies on patients with KIT-mutated melanoma treated with nilotinib.
  • In vitro experiments using melanoma cell lines dependent on oncogenic KIT.
  • Analysis of in situ data from a clinical trial to confirm FGF2 expression and MEK-ERK activation.

Main Results:

  • FGF2 axis activation was identified as a potential mechanism of resistance to KIT inhibition.
  • FGF2 lessened the effect of KIT inhibition on cell viability by inhibiting BIM expression through MAPK pathway activation.
  • MEK inhibitor addition reversed FGF2-driven resistance in all tested KIT mutants.
  • FGF2 expression and MEK-ERK activation were confirmed in melanoma patient samples.

Conclusions:

  • Combined inhibition of KIT with FGFR or MEK inhibitors represents a potential next-step clinical strategy for treating KIT-mutant melanoma.
  • Targeting the FGF2/MAPK pathway in conjunction with KIT inhibition may overcome therapeutic resistance.
Keywords:
FGF2 BIMKITMAPKmelanomatargeted therapy resistance

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