title: Targeting of RET oncogene by naphthalene diimide-mediated gene promoter G-quadruplex stabilization exerts anti-tumor activity in oncogene-addicted human medullary thyroid cancer.
abstract: Medullary thyroid cancer (MTC) relies on the aberrant activation of RET proto-oncogene. Though targeted approaches (i.e., tyrosine kinase inhibitors) are available, the absence of complete responses and the onset of resistance mechanisms indicate the need for novel therapeutic interventions. Due to their role in regulation of gene expression, G-quadruplexes (G4) represent attractive targets amenable to be recognized or stabilized by small molecules. Here, we report that exposure of MTC cells to a tri-substituted naphthalene diimide (NDI) resulted in a significant antiproliferative activity paralleled by inhibition of RET expression. Biophysical analysis and gene reporter assays showed that impairment of RET expression was consequent to the NDI-mediated stabilization of the G4 forming within the gene promoter. We also showed for the first time that systemic administration of the NDI in mice xenotransplanted with MTC cells resulted in a remarkable inhibition of tumor growth in vivo. Overall, our findings indicate that NDI-dependent RET G4 stabilization represents a suitable approach to control RET transcription and delineate the rationale for the development of G4 stabilizing-based treatments for MTC as well as for other tumors in which RET may have functional and therapeutic implications.
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lopergolo
authors.affiliation: Department of Molecular Medicine, University of Padua, 35121, Padova, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Perrone
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Tortoreto
authors.affiliation: Department of Chemistry, University of Pavia, 27100, Pavia, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Doria
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy.
authors.forename: Giovanni L
authors.initials: GL
authors.lastname: Beretta
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuco
authors.affiliation: Department of Chemistry, University of Pavia, 27100, Pavia, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Freccero
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Borrello
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lanzi
authors.affiliation: Department of Molecular Medicine, University of Padua, 35121, Padova, Italy.
authors.forename: Sara N
authors.initials: SN
authors.lastname: Richter
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Folini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018278:Carcinoma, Neuroendocrine / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D054856:G-Quadruplexes; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007094:Imides / Q000737:chemistry*; D008024:Ligands; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009281:Naphthalenes / Q000737:chemistry*; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*
chemical_list: D000970:Antineoplastic Agents; D007094:Imides; D008024:Ligands; C000715470:MAS1 protein, human; D009281:Naphthalenes; D000090063:Proto-Oncogene Mas; C542131:naphthalenediimide; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: G-quadruplex; RET oncogene; gene promoter; medullary thyroid cancer; naphthalene diimide