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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Secondary Tumors Arising in Patients Undergoing BRAF Inhibitor Therapy Exhibit Increased BRAF-CRAF Heterodimerization

Lise Boussemart1, Isabelle Girault2, Hélène Malka-Mahieu3

  • 1Département de médecine oncologique, Gustave Roussy, Villejuif, France. INSERM, U981, Villejuif, France.

Cancer Research
|January 31, 2016
PubMed

Insights

BRAF inhibitors treat melanoma but can cause secondary skin tumors. Increased BRAF-CRAF complex formation is linked to these BRAF inhibitor-induced tumors, suggesting it could be a biomarker.

Area of Science:

  • Oncology
  • Dermatology
  • Molecular Biology

Background:

  • BRAF inhibitors (BRAFi) are effective against metastatic melanoma.
  • BRAFi treatment can paradoxically lead to secondary skin tumors, including benign and malignant types.
  • The molecular mechanisms underlying BRAFi-induced tumorigenesis require further investigation.

Purpose of the Study:

  • To characterize the emergence and molecular features of secondary tumors in patients treated with BRAFi.
  • To investigate the role of BRAF-CRAF heterodimerization in BRAFi-induced tumor formation.
  • To identify potential biomarkers for predicting or monitoring BRAFi-induced secondary tumors.

Main Methods:

  • Molecular characterization and genotyping of 73 tumors from 31 patients undergoing BRAFi therapy.
  • Analysis of oncogenic RAS mutations in tumor samples.
  • Proximity ligation assays to assess BRAF-CRAF heterodimerization in tumor samples from treated and untreated patients.

Main Results:

  • BRAFi therapy was associated with the development of various skin tumors, including verrucous papillomas, keratoacanthomas, and squamous cell carcinomas (SCC).
  • A subset of patients developed distinct tumors like lymph node metastasis, new melanomas, and mucosal SCCs.
  • Oncogenic RAS mutations were prevalent in tumors from both BRAFi-treated and untreated patients.
  • Increased BRAF-CRAF heterodimerization was observed in tumors from BRAFi-treated patients compared to controls.

Conclusions:

  • BRAF-CRAF complex formation is significantly associated with BRAFi treatment.
  • This BRAF-CRAF complex formation may serve as a biomarker for BRAFi-induced cutaneous and extracutaneous tumor development.
  • Understanding these mechanisms is crucial for managing side effects of BRAFi therapy in melanoma patients.

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