title: Molecular Understanding of the Acquisition of Resistance to Anti-cancer Drugs Associated with the Exacerbation of Cancer.
abstract: Gefitinib and erlotinib target the ATP cleft in the tyrosine kinase EGFR, which is overexpressed in 40-80 percent of non-small-cell lung cancer (NSCLC) and many other epithelial cancers. However, the application of gefitinib is ultimately limited by the emergence of mutations and other molecular mechanisms conferring drug resistance. Furthermore, it has been considered that acquired resistance to gefitinib is associated with a clinically significant risk of accelerated disease progression. We previously established a new gefitinib-resistant NSCLC cell line, HCC827GR, which harbors the T790M mutation. Using HCC827GR, we found that the inhibition of adenosine A2a receptors of NSCLC regulated cancer proliferation and exacerbation, indicating that adenosine A2a receptors may be new targets for a novel strategy in NSCLC therapy. These findings suggest that multilayered crosstalk between G-protein coupled receptors (GPCRs) and EGFR may play an important role in regulating downstream signaling molecules that are implicated in the development of gefitinib-resistant NSCLC.
authors.affiliation: Department of Pharmacology, Hoshi University, School of Pharmacy and Pharmaceuteutical Sciences.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kuzumaki
authors.forename: Michiko
authors.initials: M
authors.lastname: Narita
authors.forename: Daigo
authors.initials: D
authors.lastname: Ikegami
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
mesh_terms: D000255:Adenosine Triphosphate; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000502:physiology; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D011505:Protein-Tyrosine Kinases; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D020239:Receptor Cross-Talk; D043705:Receptor, Adenosine A2A; D043562:Receptors, G-Protein-Coupled / Q000502:physiology
chemical_list: D011799:Quinazolines; D043705:Receptor, Adenosine A2A; D043562:Receptors, G-Protein-Coupled; D000255:Adenosine Triphosphate; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib