title: Resistance mechanisms after tyrosine kinase inhibitors afatinib and crizotinib in non-small cell lung cancer, a review of the literature.
abstract: Targeted treatment of advanced non-small cell lung cancer patients with afatinib in EGFR mutation or crizotinib in ALK break positive patients results in profound tumor responses but inevitably induces resistance. In this review we present currently known resistance mechanisms for afatinib and crizotinib two recently approved drugs. Resistance mechanisms identified for afatinib include c-MET amplification and the V843I EGFR mutation. Expression of FGFR1, increased IL6R/JAK/STAT signaling, enhanced interference with aerobic glycolysis and autophagy are associated with resistance to afatinib. Most common resistance mechanisms for ALK break positive cases are gatekeeper mutations in the ALK gene. Also activation of the EGFR pathway, KRAS mutations, the autophagy pathway and epithelial mesenchymal transition (EMT), have been associated with resistance. Many of the proposed resistance mechanisms need to be functionally studied to proof a causative relationship with resistance.
authors: Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Netherlands. Electronic address: a.j.van.der.wekken@umcg.nl.
authors: A J
authors: AJ
authors: van der Wekken
authors: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Netherlands.
authors: A
authors: A
authors: Saber
authors: Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Netherlands.
authors: T J N
authors: TJ
authors: Hiltermann
authors: Department of Genetics, University of Groningen, University Medical Center Groningen, Netherlands.
authors: K
authors: K
authors: Kok
authors: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Netherlands.
authors: A
authors: A
authors: van den Berg
authors: Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Netherlands.
authors: H J M
authors: HJ
authors: Groen
mesh_terms: D000077716:Afatinib; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011799:Quinazolines; D000077716:Afatinib; D000077547:Crizotinib; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; Afatinib resistance; Crizotinib resistance; EGFR; NSCLC; Targeted therapy