A melanoma subtype with intrinsic resistance to BRAF inhibition identified by receptor tyrosine kinases gene-driven classification

Matteo Dugo, Gabriella Nicolini, Gabrina Tragni, Ilaria Bersani, Antonella Tomassetti, Valentina Colonna, Michele Del Vecchio, Filippo De Braud, Silvana Canevari, Andrea Anichini, Marialuisa Sensi

Research output: Contribution to journalArticle

Abstract

Dysregulation of receptor tyrosine kinases (RTKs) contributes to several aspects of oncogenesis including drug resistance. In melanoma, distinct RTKs have been involved in BRAF inhibitors (BRAFi) resistance, yet the utility of RTKs expression pattern to identify intrinsically resistant tumors has not been assessed. Transcriptional profiling of RTKs and integration with a previous classification, reveals three robust subtypes in two independent datasets of melanoma cell lines and one cohort of melanoma samples. This classification was validated by Western blot in a panel of patient-derived melanoma cell lines. One of the subtypes identified here for the first time displayed the highest and lowest expression of EGFR and ERBB3, respectively, and included BRAF-mutant tumors all intrinsically resistant to BRAFi PLX4720, as assessed by analysis of the Cancer Cell Line Encyclopedia pharmacogenomic study and by in vitro growth inhibition assays. High levels of EGFR were detected, even before therapy, in tumor cells of one of three melanoma patients unresponsive to BRAFi. Use of different pharmacological inhibitors highlighted the relevance of PI3K/mTOR signaling for growth of this PLX4720-resistant subtype. Our results identify a specific molecular profile of melanomas intrinsically resistant to BRAFi and suggest the PI3K/ mTOR pathway as a potential therapeutic target for these tumors.

Original languageEnglish
Pages (from-to)5118-5133
Number of pages16
JournalOncotarget
Volume6
Issue number7
Publication statusPublished - 2015

Keywords

  • BRAF
  • BRAF inhibitors
  • Drug resistance
  • Melanoma subtypes
  • Receptor tyrosine kinases

ASJC Scopus subject areas

  • Oncology

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