Article: article from journal or magazin.
Review (review): journal as complete as possible of one specific subject, written based on exhaustive analyses from published work.
ALK inhibitors in the treatment of advanced NSCLC.
Cancer Treatment Reviews
Publication types: Journal Article ; ReviewPublication Status: ppublishDocument Type: Review
Pharmacologic agents that target protein products of oncogenes in tumors are playing an increasing clinical role in the treatment of cancer. Currently, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. Subsequently other genetic abnormalities with "driver" characteristics - implying transforming and tumor maintenance capabilities have been extensively reported in several small distinct subsets of NSCLC. Among these rare genetic changes, anaplastic lymphoma kinase (ALK) gene rearrangements, most often consisting in a chromosome 2 inversion leading to a fusion with the echinoderm microtubule-associated protein like 4 (EML4) gene, results in the abnormal expression and activation of this tyrosine kinase in the cytoplasm of cancer cells. This rearrangement occurs in 2-5% of NSCLC, predominantly in young (50 years or younger), never- or former-smokers with adenocarcinoma. This aberration most commonly occurs a independently of EGFR and KRAS gene mutations. A fluorescent in situ hybridization assay was approved by the US Food and Drug Administration (FDA) as the standard method for the detection of ALK gene rearrangement in clinical practice and is considered the gold standard. Crizotinib, a first-in-class dual ALK and c-MET inhibitor, has been shown to be particularly effective against ALK positive NSCLC, showing dramatic and prolonged responses with low toxicity, predominantly restricted to the gastro-intestinal and visual systems, and generally self-limiting or easily managed. However, resistance to crizotinib inevitably emerges. The molecular mechanisms of resistance are currently under investigation, as are therapeutic approaches including crizotinib-based combination therapy and novel agents such as Hsp90 inhibitors. This review aims to present the current knowledge on this fusion gene, the clinic-pathological profile of ALK rearranged NSCLC, and to review the existing literature on ALK inhibitors, focusing on their role in the treatment of NSCLC.
Adenocarcinoma/drug therapy, Antineoplastic Agents/pharmacology, Antineoplastic Agents/therapeutic use, Carcinoma, Non-Small-Cell Lung/drug therapy, Carcinoma, Non-Small-Cell Lung/genetics, Chromosome Inversion, Chromosomes, Human, Pair 2/genetics, Drug Resistance, Neoplasm, Enzyme Activation, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms/drug therapy, Lung Neoplasms/genetics, Oncogene Proteins, Fusion/antagonists & inhibitors, Oncogene Proteins, Fusion/genetics, Protein Kinase Inhibitors/pharmacology, Protein Kinase Inhibitors/therapeutic use, Pyrazoles/pharmacology, Pyrazoles/therapeutic use, Pyridines/pharmacology, Pyridines/therapeutic use, Receptor Protein-Tyrosine Kinases/antagonists & inhibitors, Receptor Protein-Tyrosine Kinases/genetics
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