Antigene MYCN Silencing by BGA002 Inhibits SCLC Progression Blocking mTOR Pathway and Overcomes Multidrug Resistance.

Autor: Bortolotti S; BIOGENERA SpA, R&D Department, 40064 Bologna, Italy., Angelucci S; BIOGENERA SpA, R&D Department, 40064 Bologna, Italy., Montemurro L; Pediatric Oncology and Hematology Unit, IRCCS, University Hospital of Bologna, 40138 Bologna, Italy., Bartolucci D; BIOGENERA SpA, R&D Department, 40064 Bologna, Italy., Raieli S; Oncodesign SA, 21079 Dijon, France., Lampis S; Bambino Gesu Children's Hospital, IRCCS, Research Laboratories-Oncohematology Department, 00165 Rome, Italy., Amadesi C; BIOGENERA SpA, R&D Department, 40064 Bologna, Italy., Scardovi A; BIOGENERA SpA, R&D Department, 40064 Bologna, Italy., Nieddu G; BIOGENERA SpA, R&D Department, 40064 Bologna, Italy., Cerisoli L; BIOGENERA SpA, R&D Department, 40064 Bologna, Italy., Paganelli F; Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy.; CNR Institute of Molecular Genetics 'Luigi Luca Cavalli-Sforza', Unit of Bologna, 40129 Bologna, Italy., Chiarini F; Department of Bio-medical, Metabolic and Neural Sciences, Section of Human Morphology, University of Modena and Reggio Emilia, 41125 Modena, Italy., Teti G; Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy., Falconi M; Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy., Pession A; IRCCS, Pediatric Unit, University Hospital of Bologna, 40138 Bologna, Italy., Hrelia P; Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy., Tonelli R; Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2023 Feb 03; Vol. 15 (3). Date of Electronic Publication: 2023 Feb 03.
DOI: 10.3390/cancers15030990
Abstrakt: Small-cell lung cancer (SCLC) is the most aggressive lung cancer type, and is associated with smoking, low survival rate due to high vascularization, metastasis and drug resistance. Alterations in MYC family members are biomarkers of poor prognosis for a large number of SCLC. In particular, MYCN alterations define SCLC cases with immunotherapy failure. MYCN has a highly restricted pattern of expression in normal cells and is an ideal target for cancer therapy but is undruggable by traditional approaches. We propose an innovative approach to MYCN inhibition by an MYCN -specific antigene-PNA oligonucleotide (BGA002)-as a new precision medicine for MYCN -related SCLC. We found that BGA002 profoundly and specifically inhibited MYCN expression in SCLC cells, leading to cell-growth inhibition and apoptosis, while also overcoming multidrug resistance. These effects are driven by mTOR pathway block in concomitance with autophagy reactivation, thus avoiding the side effects of targeting mTOR in healthy cells. Moreover, we identified an MYCN -related SCLC gene signature comprehending CNTFR , DLX5 and TNFAIP3 , that was reverted by BGA002. Finally, systemic treatment with BGA002 significantly increased survival in MYCN -amplified SCLC mouse models, including in a multidrug-resistant model in which tumor vascularization was also eliminated. These findings warrant the clinical testing of BGA002 in MYCN -related SCLC.
Competing Interests: R. Tonelli and A. Pession are BIOGENERA shareholders. C. Amadesi, D. Bartolucci, S. Bortolotti, S. Angelucci, A. Scardovi, G. Nieddu, and L. Cerisoli are employed at BIOGENERA. The authors declare no potential conflicts of interest.
Databáze: MEDLINE
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