Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors.
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.
Carlomagno
Francesca
F
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.
Guida
Teresa
T
Anaganti
Suresh
S
Vecchio
Giancarlo
G
Fusco
Alfredo
A
Ryan
Anderson J
AJ
Billaud
Marc
M
Santoro
Massimo
M
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
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