Reference Detail

Ref Type

Journal Article

PMID

(23811235)

Authors

Mologni L, Redaelli S, Morandi A, Plaza-Menacho I, Gambacorti-Passerini C

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular and cellular endocrinology	377	1-2	2013 Sep 5	1-6	Mol Cell Endocrinol

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
RET	V804M	missense	gain of function	RET V804M lies within the protein kinase domain of the Ret protein (UniProt.org). V804M confers a gain of function on the Ret protein, resulting in increased kinase activity, cell transformation (PMID: 16469774), and is considered a gatekeeper due to lack of response to some inhibitors, including cabozantinib and vandetanib (PMID: 23811235, PMID: 27712045).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET C634R	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, transformed human cell lines expressing RET C634R demonstrated sensitivity to Iclusig (ponatinib) (PMID: 23811235).	23811235
RET mutant	colorectal cancer	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) demonstrated efficacy in RET mutant positive colorectal cancer cell lines (PMID: 23811235).	23811235
RET V804L	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, transformed human cell lines expressing RET V804L demonstrated sensitivity to Iclusig (ponatinib) (PMID: 23811235).	23811235
RET V804M	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, transformed human cell lines expressing RET V804M demonstrated sensitivity to Iclusig (ponatinib) (PMID: 23811235).	23811235