title: Beyond EGFR and ALK inhibition: unravelling and exploiting novel genetic alterations in advanced non small-cell lung cancer.
abstract: During the last decade, thoracic oncology has witnessed an unprecedented outburst of knowledge regarding molecular biology of non small-cell lung cancer (NSCLC). The implementation of high-throughput sequencing analysis and genomic technologies has led to the identification of novel molecular events that characterize NSCLC transformation and may represent critical oncogenic drivers amenable to targeted therapy. Among these, the presence of activating mutations of the epidermal growth factor receptor (EGFR) gene and of chromosomic rearrangements in the anaplastic-lymphoma kinase (ALK) proto-oncogene, have been the first well characterized genetic alterations with corresponding targeted agents to enter the clinical arena. Nevertheless, in the recent years a number of other oncogenic drivers beyond EGFR and ALK inhibition have emerged as novel molecular targets with potential therapeutic implications, including mutations in the genes KRAS, BRAF, HER2, PI3KCA and DDR2, as well as ROS1 and RET rearrangements and MET, HER2 and FGFR1 gene amplifications. The aim of this review is to provide comprehensive information on the novel therapeutic targets identified by recent preclinical evidence and to discuss developments in molecular treatments targeting these oncogenic drivers or actionable mutations beyond EGFR and ALK in advanced NSCLC.
authors.affiliation: Cancer Research UK Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom; Department of Medical Oncology, University Hospital of South Manchester Foundation Trust, Manchester M23 9LT, United Kingdom.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Califano
authors.affiliation: Cancer Research UK Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom.
authors.forename: Aidalena
authors.initials: A
authors.lastname: Abidin
authors.affiliation: Cancer Research UK Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom.
authors.forename: Noor-Ul-Ain
authors.initials: NU
authors.lastname: Tariq
authors.affiliation: Medical Oncology Unit, 2nd Department of Medicine, Attikon University Hospital, Haidari, Athens, Greece.
authors.forename: Panagiota
authors.initials: P
authors.lastname: Economopoulou
authors.affiliation: Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Metro
authors.affiliation: Department of Medical Oncology, University of Athens School of Medicine, Athens, Greece. Electronic address: gmountzios@gmail.com.
authors.forename: Giannis
authors.initials: G
authors.lastname: Mountzios
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018773:Genes, erbB-1; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D058990:Molecular Targeted Therapy; D000090063:Proto-Oncogene Mas; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; BRAF; DDR2; EGFR; HER2; KRA; Non-small cell lung cancer; Oncogenic drivers; PI3KCA; ROS1