Non‐small cell lung cancer (NSCLC) is the primary cause of cancer death worldwide. Despite developments in chemotherapy and targeted therapies, the 5‐year survival rate has remained at approximately 16% for the last four decades. NSCLC is a heterogeneous group of tumors that, through mutations and drivers, also demonstrate intra‐tumor heterogeneity. Thus, current treatment approaches revolve around targeting these oncogenes, often using small molecule inhibitors and chemotherapeutics. However, the efficacy of these therapies has been crippled by acquired and inherent drug‐resistance in the tumor, accompanied by increased therapeutic dosages and subsequent devastating off‐target effects for patients. Evidently, there is a critical need for developing treatment methodologies more effective than the current standard of care. Fortunately, RNA interference, particularly small interfering RNA (siRNA), presents an alternative of silencing specific oncogenes to control tumor growth. Although siRNA therapy is subject to rapid degradation and poor internalization in vivo, nanoparticles can serve as nontoxic and efficient delivery vehicles, even introducing combinational delivery of multiple therapeutic agents. Indeed, siRNA‐nanoconstructs possess extraordinary potential as an innovative modality to address clinical needs. This state‐of‐the‐art review summarizes the recent advancements in the development of novel nanosystems for delivering siRNA to NSCLC tumors and analyzes the efficacy of representative examples. By illuminating the most promising biomarkers for silencing, we hope to streamline current therapeutic efforts and highlight powerful translational opportunities to combat NSCLC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology‐Inspired Nanomaterials > Lipid‐Based Structures Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Non-small Cell Lung Cancer (NSCLC) patients who express EGFR activating mutations are treated with tyrosine kinase inhibitors (TKI) and have a median overall survival time of 22 months. TKI therapy showed only moderate success with poor (37%) survival rate. On the other hand, TKI therapy is ineffective in patients with active KRAS mutation. Acquired drug resistance is one of the major reasons for the failure of the TKI therapy. Studies have shown that overexpression of AXL is one of the possible reasons for the drug resistance. In our previous studies, we have shown that AXL inhibition in NSCLC drug-resistant cells resulted in FN14 survival activation. Subsequently, we have demonstrated that co-inhibition of both AXL and FN14 resulted in increased therapeutic efficacy. Based on these studies, we recognize that both AXL and FN14 play important role in proliferation, invasion and survival pathways. Therefore, synergistic co-inhibition of AXL-FN14 is a viable therapeutic strategy for treating NSCLC. In the present study, we compared the efficacy of inhibition of AXL and FN14 by siRNA (using nanoparticle delivery vehicles) and small-molecule inhibitors in A549 mouse xenografts. Our data further confirms that co-inhibition is effective and results in tumor volume reduction. The details of this study provide a rationale for enhanced treatment of drug resistant NSCLC. Citation Format: Dhananjay Suresh, Soumavo Mukherjee, Ajit Zambre, Shreya Ghoshdastidar, Sairam Yadavilli, Anandhi Upendran, Raghuraman Kannan. Co-inhibition of AXL and FN14 by pharmacologic inhibitors or genetic inhibition in NSCLC mice models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4891.