Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer.

Sara Elena Rebuzzi,Marco Tagliamento,Arsela Prelaj,Angela Alama,Massimiliano Grassi,Chiara Dellepiane,Elisa Bennicelli,Lodovica Zullo,Luca Longo,Veronica Murianni,Umberto Malapelle,Giovanni Rossi,Simona Coco,Maria Giovanna Dal Bello,Carlo Genova

doi:10.3390/ijms22052625

Abstract

In the scenario of systemic treatment for advanced non-small cell lung cancer (NSCLC) patients, one of the most relevant breakthroughs is represented by targeted therapies. Throughout the last years, inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-Ros oncogene 1 (ROS1), and V-raf murine sarcoma viral oncogene homolog B (BRAF) have been approved and are currently used in clinical practice. However, other promising molecular drivers are rapidly emerging as therapeutic targets. This review aims to cover the molecular alterations with a potential clinical impact in NSCLC, including amplifications or mutations of the mesenchymal–epithelial transition factor (MET), fusions of rearranged during transfection (RET), rearrangements of the neurotrophic tyrosine kinase (NTRK) genes, mutations of the Kirsten rat sarcoma viral oncogene (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), as well as amplifications or mutations of human epidermal growth factor receptor 2 (HER2). Additionally, we summarized the current status of targeted agents under investigation for such alterations. This revision of the current literature on emerging molecular targets is needed as the evolving knowledge on novel actionable oncogenic drivers and targeted agents is expected to increase the proportion of patients who will benefit from tailored therapeutic approaches.

Highlights

Since the discovery of actionable molecular alterations, the therapeutic approach of advanced non-small cell lung cancer (NSCLC) patients has been constantly evolving throughout the years
The neurotrophic tyrosine kinase (NTRK) fusions can be studied with different methods, among which IHC is one of the most widespread used and characterized by high sensitivity (95 to 100%) and specificity (93% to 100%); these data derive from very small studies, this technique can be considered a good screening tool as of today, given the rarity of NTRK gene alterations [58,62]
Another relevant diagnostic tool is represented by fluorescence in situ hybridization (FISH), which may be helpful when the histologic tumor type is known to frequently harbor an NTRK fusion, this may not be the best option in NSCLC due to its aforementioned low prevalence [59,62]

Summary

Introduction

Since the discovery of actionable molecular alterations, the therapeutic approach of advanced non-small cell lung cancer (NSCLC) patients has been constantly evolving throughout the years. As the current paramount of molecularly driven treatment of NSCLC 4.0/). This review aims to summarize the current state of the art and future directions of novel emerging therapeutic targets for NSCLC, with mention to the involved molecular pathways and the potential therapeutic strategies assessed in clinical studies. We performed a comprehensive literature search to collect relevant data on PubMed for published articles and the most relevant international conferences involving lung cancer from the American. Association for Cancer Research (AACR), American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and World Conference on Lung Cancer (WCLC), looking for the most updated and complete information.

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