Journal
ONCOGENE
Volume 23, Issue 36, Pages 6056-6063Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1207810
Keywords
thyroid; tyrosine kinase inhibitors; RET; MEN2
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We have recently demonstrated that the pyrazolopyrimidines PP1 and PP2 and the 4-anilinoquinazoline ZD6474 display a strong inhibitory activity (IC(50)less than or equal to100 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 IC50: 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.
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