Silencing AXL by covalent siRNA-gelatin-antibody nanoconjugate inactivates mTOR/EMT pathway and stimulates p53 for TKI sensitization in NSCLC.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality with the 5-year survival rate at a dismal 16% for the past 40 years. Drug resistance is a major obstacle to achieving long-term patient survival. Identifying and validating molecular biomarkers responsible for resistance and thereby adopting multi-directional therapy is necessary to improve the survival rate. Previous studies indicated ~20% of tyrosine kinase inhibitor (TKI) resistant NSCLC patients overexpress AXL with increase in EMT and decrease in p53 expression. To overcome the resistance, we designed gelatin nanoparticles covalently conjugated with EGFR targeting antibody and siRNA (GAbsiAXL). GAbsiAXL efficiently silences AXL, decreases mTOR and EMT signaling with concomitant increase in p53 expression. Because of the molecular changes, the AXL silencing sensitizes the cells to TKI. Our results show AXL overexpression has an important role in driving TKI resistance through close association with energy-dependent mitochondrial pathways. Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality with the 5-year survival rate remains a dismal 16% for the past 40 years. Drug resistance is a major obstacle to achieving long-term patient survival. Identifying the various molecular determinants of resistance and thereby adopting multi-drug therapy is necessary to improve the survival rate. Previous studies indicated TKI resistant NSCLC, overexpress AXL with increase in EMT and decrease in p53 tumor suppressor protein. To overcome the resistance, we designed gelatin nanoparticle covalently conjugated with EGFR antibody and siRNA (GAbsiAXL). Our studies showed that GAbsiAXL efficiently silences AXL in cells. Treatment of drug-resistant cells with GAbsiAXL reduces mTOR and EMT signaling with concomitant increase in p53 expression. Because of the molecular changes, the AXL silencing sensitizes the cell to TKI by 2-fold. Our results show AXL overexpression has an important role in driving TKI resistance through close association with energy-dependent mitochondrial pathways. Unlabelled Image [ABSTRACT FROM AUTHOR]