title: Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors.
abstract: We have recently demonstrated that the pyrazolopyrimidines PP1 and PP2 and the 4-anilinoquinazoline ZD6474 display a strong inhibitory activity (IC(50)< or =100 nM) towards constitutively active oncogenic RET kinases. Here, we show that most oncogenic MEN2-associated RET kinase mutants are highly susceptible to PP1, PP2 and ZD6474 inhibition. In contrast, MEN2-associated swap of bulky hydrophobic leucine or methionine residues for valine 804 in the RET kinase domain causes resistance to the three compounds. Substitution of valine 804 with the small amino- acid glycine renders the RET kinase even more susceptible to inhibition (ZD6474 IC(50): 20 nM) than the wild-type kinase. Our data identify valine 804 of RET as a structural determinant mediating resistance to pyrazolopyrimidines and 4-anilinoquinazolines.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, University 'Federico II', c/o Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, via S. Pansini 5, Napoli, Italia.
authors.forename: Francesca
authors.initials: F
authors.lastname: Carlomagno
authors.forename: Teresa
authors.initials: T
authors.lastname: Guida
authors.forename: Suresh
authors.initials: S
authors.lastname: Anaganti
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Vecchio
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ryan
authors.forename: Marc
authors.initials: M
authors.lastname: Billaud
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
mesh_terms: D018276:Carcinoma, Medullary / Q000235:genetics*; D020134:Catalytic Domain; D002460:Cell Line; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008934:Mitogens / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics*; D014633:Valine / Q000235:genetics
chemical_list: C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; C412373:AG 1879; D004791:Enzyme Inhibitors; D008934:Mitogens; D010880:Piperidines; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D011799:Quinazolines; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D014633:Valine; C452423:vandetanib