Recent advances in tiling array and high throughput analyses revealed that at least 87.3 % of the human genome is actively transcribed, though <3 % of the human genome encodes proteins. This unexpected truth suggests that most of the transcriptome is constituted by noncoding RNA. Among them, high-resolution microarray and massively parallel sequencing analyses identified long noncoding RNAs (lncRNAs) as nonprotein-coding transcripts. lncRNAs are largely polyadenylated and >200 nucleotides in length transcripts, involved in gene expression through epigenetic and transcriptional regulation, splicing, imprinting and subcellular transport. Although lncRNAs functions are largely uncharacterized, accumulating data indicate that they are involved in fundamental biological functions. Conversely, their dysregulation has increasingly been recognized to contribute to the development and progression of several human malignancies, especially lung cancer, which represents the leading cause of cancer-related deaths worldwide. We conducted a comprehensive review of the published literature focusing on lncRNAs function and disruption in nonsmall cell lung cancer biology, also highlighting their value as biomarkers and potential therapeutic targets. lncRNAs are involved in NSCLC pathogenesis, modulating fundamental cellular processes such as proliferation, cell growth, apoptosis, migration, stem cell maintenance and epithelial to mesenchymal transition, also serving as signaling transducers, molecular decoys and scaffolds. Also, lncRNAs represent very promising biomarkers in early-stage NSCLC patients and may become particularly useful in noninvasive screening protocols. lncRNAs may be used as predictive biomarkers for chemotherapy and targeted therapies sensitivity. Furthermore, selectively targeting oncogenic lncRNAs could provide a new therapeutic tool in treating NSCLC patients. lncRNAs disruption plays a pivotal role in NSCLC development and progression. These molecules also serve as diagnostic, prognostic and predictive biomarkers. Characterization of lncRNA genes and their mechanisms of action will enable us to develop a more comprehensive clinical approach, with the final goal to benefit our patients.

Lung cancer is the leading cause of cancer deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 80% of all lung cancers. Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the deadliest cancer-related proteins and plays a pivotal role in the most aggressive and lethal human cancers, including lung adenocarcinoma where it represents one of the most frequently mutated oncogene. Although therapeutic progresses have made an impact over the last decade, median survival for patients with advanced lung cancer remains disappointing, with a 5-year worldwide survival rate of <15%. For more than 20 years it has been recognized that constitutively active signaling downstream of KRAS is a fundamental driver of lung tumorigenesis. However, years of pursuit have failed to yield a drug that can safely curb KRAS activity; up to now no approved therapies exist for KRAS-mutant NSCLC. The aim of this review is to discuss the current knowledge of KRAS-mutated NSCLC, touching upon KRAS clinical relevance as a prognostic and predictive biomarker, with an emphasis on novel therapeutic approaches for the treatment of KRAS-variant NSCLC.

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The identification of epidermal growth factor receptor (EGFR) mutations represented a fundamental step forward in the treatment of advanced non-small cell lung cancer (NSCLC) as they define a subset of patients who benefit from the administration of specifically designed targeted therapies. The inhibition of mutant EGFR through EGFR-tyrosine kinase inhibitors (TKIs), either reversible, first-generation gefitinib and erlotinib, or irreversible, second-generation afatinib, has dramatically improved the prognosis of patients harboring this specific genetic alteration, leading to unexpected clinical benefit. Unfortunately, virtually all patients who initially respond to treatment develop acquired resistance to EGFR-TKIs within 9–14 months. The EGFR T790M secondary mutation has emerged as a cause of treatment failure in approximately 60% of resistant cases. To date, several compounds designed with the aim to overcome T790M-mediated resistance are under clinical investigation. The aim of this review is to discuss emerging data regarding the third-generation EGFR-TKI, osimertinib, for the treatment of EGFR T790M mutant advanced NSCLC.