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|Ref Type||Journal Article|
|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.|
|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.|
|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 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 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 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|