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

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 family members are biomarkers of poor prognosis for a large number of SCLC. In particular, alterations define SCLC cases with immunotherapy failure. 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 inhibition by an -specific antigene-PNA oligonucleotide (BGA002)-as a new precision medicine for -related SCLC. We found that BGA002 profoundly and specifically inhibited 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 -related SCLC gene signature comprehending , and , that was reverted by BGA002. Finally, systemic treatment with BGA002 significantly increased survival in -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 -related SCLC.