Identification of RET kinase inhibitors as potential new treatment for sporadic and inherited thyroid cancer.
The RET gene is frequently mutated in papillary thyroid carcinoma and in medullary thyroid carcinoma. We have identified three different anti-RET drugs: two pyrazolo-pyrimidines, PP1 and PP2 and an anilinoquinazoline, ZD6474 (AstraZeneca). These compounds are able to inhibit RET kinase activity in vitro (IC50 dose 100 nM) and in vivo and they can prevent RET mediated transformation. Finally, mutation of RET V804 to methionine or leucine, found in MTC patients, induces resistance to the three drugs.
Carlomagno
F
F
Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università degli Studi di Napoli Federico II, 80131 Napoli, Italy. persfra@tin.it
Santoro
M
M
D018276:Carcinoma, Medullary / Q000188:drug therapy / Q000235:genetics; D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics*; D012680:Sensitivity and Specificity; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016896:Treatment Outcome
D010880:Piperidines; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C452423:vandetanib