RET kinase is aberrantly activated in thyroid cancers and in rare cases of lung and colon cancer, and has been validated as a molecular target in these tumors. Vandetanib was recently approved for the treatment of medullary thyroid cancer. However, vandetanib is ineffective in vitro against RET mutants carrying bulky aminoacids at position 804, the gatekeeper residue, similarly to drug-resistant BCR-ABL mutants in chronic myeloid leukemia. Ponatinib is a multi-target kinase inhibitor that was recently approved for treatment-refractory Philadelphia-positive leukemia. We show here potent inhibition of oncogenic RET by ponatinib, including the drug-insensitive V804M/L mutants. Ponatinib inhibited the growth of RET+ and BCR-ABL+ cells with similar potency, while not affecting RET-negative cells. Both in biochemical and in cellular assays ponatinib compared favorably with known RET inhibitors, such as vandetanib, cabozantinib, sorafenib, sunitinib and motesanib, used as reference compounds. We suggest that ponatinib should be considered for the treatment of RET+ tumors, in particular those expressing vandetanib-resistant V804M/L mutations. © 2013 Elsevier Ireland Ltd.

Mologni, L., Redaelli, S., Morandi, A., Plaza Menacho, I., & Gambacorti Passerini, C. (2013). Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase. MOLECULAR AND CELLULAR ENDOCRINOLOGY, 377(1-2), 1-6 [10.1016/j.mce.2013.06.025].

Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase

MOLOGNI, LUCA
;
REDAELLI, SARA;GAMBACORTI PASSERINI, CARLO
2013

Abstract

RET kinase is aberrantly activated in thyroid cancers and in rare cases of lung and colon cancer, and has been validated as a molecular target in these tumors. Vandetanib was recently approved for the treatment of medullary thyroid cancer. However, vandetanib is ineffective in vitro against RET mutants carrying bulky aminoacids at position 804, the gatekeeper residue, similarly to drug-resistant BCR-ABL mutants in chronic myeloid leukemia. Ponatinib is a multi-target kinase inhibitor that was recently approved for treatment-refractory Philadelphia-positive leukemia. We show here potent inhibition of oncogenic RET by ponatinib, including the drug-insensitive V804M/L mutants. Ponatinib inhibited the growth of RET+ and BCR-ABL+ cells with similar potency, while not affecting RET-negative cells. Both in biochemical and in cellular assays ponatinib compared favorably with known RET inhibitors, such as vandetanib, cabozantinib, sorafenib, sunitinib and motesanib, used as reference compounds. We suggest that ponatinib should be considered for the treatment of RET+ tumors, in particular those expressing vandetanib-resistant V804M/L mutations. © 2013 Elsevier Ireland Ltd.
Articolo in rivista - Articolo scientifico
Scientifica
Gatekeeper; Ponatinib; RET; Thyroid cancer; Tyrosine kinase;
English
Mologni, L., Redaelli, S., Morandi, A., Plaza Menacho, I., & Gambacorti Passerini, C. (2013). Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase. MOLECULAR AND CELLULAR ENDOCRINOLOGY, 377(1-2), 1-6 [10.1016/j.mce.2013.06.025].
Mologni, L; Redaelli, S; Morandi, A; Plaza Menacho, I; GAMBACORTI PASSERINI, C
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/53753
Citazioni
  • Scopus 69
  • ???jsp.display-item.citation.isi??? 66
Social impact