title: Ligand-triggered resistance to molecular targeted drugs in lung cancer: roles of hepatocyte growth factor and epidermal growth factor receptor ligands.
abstract: Recent advances in molecular biology have led to the identification of new molecular targets, such as epidermal growth factor receptor ( EGFR ) mutations and echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene, in lung cancer. Dramatic response has been achieved with EGFR inhibitors (gefitinib and erlotinib) and an ALK inhibitor (crizotinib) in lung cancer expressing corresponding targets. However, cancer cells acquire resistance to these drugs and cause recurrence. Known major mechanisms for resistance to molecular targeted drugs include gatekeeper mutations in the target gene and activation of bypass survival signal via receptors other than the target receptors. The latter mechanism can involve receptor gene amplification and ligand-triggered receptor activation as well. For example, hepatocyte growth factor (HGF), the ligand of a tyrosine kinase receptor Met, activates Met and the downstream PI3K/Akt pathway and triggers resistance to EGFR inhibitors in EGFR mutant lung cancer cells. Moreover, EGFR ligands activate EGFR and downstream pathways and trigger resistance to crizotinib in EML4-ALK lung cancer cells. These observations indicate that signals from oncogenic drivers (EGFR signaling in EGFR -mutant lung cancer and ALK signaling in EML4-ALK lung cancer) and ligand-triggered bypass signals (HGF-Met and EGFR ligands-EGFR, respectively) must be simultaneously blocked to avoid the resistance. This review focuses specifically on receptor activation by ligand stimulation and discusses novel therapeutic strategies that are under development for overcoming resistance to molecular targeted drugs in lung cancer.
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Ishikawa. syano@staff.kanazawa-u.ac.jp
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeuchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yamada
mesh_terms: D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors