A melanoma subtype with intrinsic resistance to BRAF inhibition identified by receptor tyrosine kinases gene-driven classification
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Matteo Dugo1, Gabriella Nicolini2, Gabrina Tragni3, Ilaria Bersani2, Antonella Tomassetti4, Valentina Colonna5, Michele Del Vecchio5, Filippo De Braud5, Silvana Canevari1, Andrea Anichini2,*, Marialuisa Sensi1,2,*
1Functional Genomics and Bioinformatics, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
2Unit of Immunobiology of Human Tumors, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
3Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
4Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
5Department of Clinical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
*These authors have contributed equally to this work
Marialuisa Sensi, e-mail: email@example.com
Andrea Anichini, e-mail: firstname.lastname@example.org
Keywords: melanoma subtypes, receptor tyrosine kinases, BRAF, BRAF inhibitors, drug resistance
Received: November 17, 2014 Accepted: December 21, 2014 Published: January 30, 2015
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.
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