Antigene IMYCN/I Silencing by BGA002 Inhibits SCLC Progression Blocking mTOR Pathway and Overcomes Multidrug Resistance

Small-cell lung cancer (SCLC) is the most aggressive form of lung cancer, is mostly associated with smoking and has a low survival rate. Among the different alterations in genes identified in SCLC, those related to the MYC family have emerged as highly relevant, alterations MYCN particularly define an aggressive and immunotherapy resistant SCLC subgroup. Due to its highly restricted expression in normal cells, MYCN is an ideal target for precision medicine, though it is difficult to target with traditional approaches. We propose an innovative approach to target MYCN in SCLC by an MYCN-specific expression inhibition at the level of gene transcription through an antigene oligonucleotide (BGA002). BGA002 exerted a potent and specific MYCN silencing in MYCN-expressing SCLC, leading to reversion of specific pathways and induction of cell death. Moreover, systemic administration of BGA002 inhibited tumor progression and significantly increased survival in SCLC mouse models, while also overcoming multidrug resistance.