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Ref Type

Journal Article

PMID

(23526464)

Authors

De Falco V, Buonocore P, Muthu M, Torregrossa L, Basolo F, Billaud M, Gozgit JM, Carlomagno F, Santoro M

Title

Ponatinib (AP24534) is a novel potent inhibitor of oncogenic RET mutants associated with thyroid cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
The Journal of clinical endocrinology and metabolism	98	5	2013 May	E811-9	J Clin Endocrinol Metab

URL

Abstract Text

The RET tyrosine kinase encoding gene acts as a dominantly transforming oncogene in thyroid carcinoma and other malignancies. Ponatinib (AP24534) is an oral ATP-competitive tyrosine kinase inhibitor that is in advanced clinical experimentation in leukemia.We tested whether ponatinib inhibited RET kinase and oncogenic activity.Ponatinib activity was studied by an in vitro RET immunocomplex kinase assay and immunoblotting. The effects of ponatinib on proliferation of human TT, MZ-CRC-1, and TPC-1 thyroid carcinoma cells, which harbor endogenous oncogenic RET alleles, and of NIH3T3 fibroblasts transfected with oncogenic RET mutants were determined. Ponatinib activity on TT cell xenografted tumors in athymic mice was measured.Ponatinib inhibited immunopurified RET kinase at the IC₅₀ of 25.8 nM (95% confidence interval [CI] = 23.15-28.77 nM). It also inhibited (IC₅₀ = 33.9 nM; 95% CI = 26.41-43.58 nM) kinase activity of RET/V804M, a RET mutant displaying resistance to other tyrosine kinase inhibitor. Ponatinib blunted phosphorylation of point-mutant and rearranged RET-derived oncoproteins and inhibited proliferation of RET-transformed fibroblasts and RET mutant thyroid carcinoma cells. Finally, after 3 weeks of treatment with ponatinib (30 mg/kg/d), the volume of TT cell (medullary thyroid carcinoma) xenografts was reduced from 133 mm³ to an unmeasurable size (difference = 133 mm³, 95% CI = -83 to 349 mm³) (P < .001). Ponatinib-treated TT cell tumors displayed a reduction in the mitotic index, RET phosphorylation, and signaling.Ponatinib is a potent inhibitor of RET kinase and has promising preclinical activity in models of RET-driven medullary thyroid carcinoma.

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Ponatinib	Ponatinib	110	30
Ponatinib + Prednisone + Vincristine Sulfate	Ponatinib Prednisone Vincristine Sulfate	0	1

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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Ponatinib	Iclusig	AP24534	ABL Inhibitor (pan) 9 BCR-ABL Inhibitor 32 DDR1 Inhibitor 10 DDR2 inhibitor 7 FGFR Inhibitor (Pan) 26 FLT3 Inhibitor 69 KIT Inhibitor 57 PDGFR-alpha Inhibitor 10 RET Inhibitor 53 SRC Inhibitor 31 VEGFR Inhibitor (Pan) 36	Iclusig (ponatinib) inhibits the Bcr-Abl fusion, and other tyrosine kinases, such as RET, DDR, VEGFR, FGFR, KIT, and FLT3 (PMID: 23526464, PMID: 25284748, PMID: 19878872). Iclusig (ponatinib) is FDA-approved for chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) as well as ABL1 T315I CML and ABL1 T315I Ph-positive ALL, and in combination with chemotherapy for newly diagnosed Ph-positive ALL (FDA.gov).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
RET	L790F	missense	unknown	RET L790F lies within the protein kinase domain of the Ret protein (UniProt.org). L790F results in ligand-independent phosphorylation of Ret (PMID: 15184865, PMID: 23526464), however, also results in cell proliferation and transformation activity similar to wild-type Ret in cell culture (PMID: 21810974, PMID: 32546069), and therefore, its effect on Ret protein function is unknown.
RET	D898V	missense	unknown	RET D898V lies within the protein kinase domain of the Ret protein (UniProt.org). D898V has been identified in the scientific literature (PMID: 23526464), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Feb 2025).

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET C634W	thyroid gland carcinoma	sensitive	Ponatinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited RET signaling and decreased growth of thyroid carcinoma cells harboring a RET C634W mutation in culture and in cell line xenograft models (PMID: 23526464).	23526464
RET mutant	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited proliferation of cancer cell lines harboring RET mutations in cultured and in cell line xenograft models (PMID: 23526464).	23526464
RET Y791F	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical - Biochemical	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET Y791F in culture (PMID: 23526464).	23526464
RET A883F	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET A883F in culture (PMID: 23526464).	23526464
RET C634Y	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited proliferation of transformed cells harboring RET C634Y in culture (PMID: 23526464).	23526464
RET D898V	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET D898V in culture (PMID: 23526464).	23526464
RET E768D	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET E768D in culture (PMID: 23526464).	23526464
RET E884K	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET E884K in culture (PMID: 23526464).	23526464
RET L790F	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET L790F in culture (PMID: 23526464).	23526464
RET M918T	thyroid gland carcinoma	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited RET signaling and decreased proliferation of thyroid carcinoma cells harboring a RET M918T mutation in culture (PMID: 23526464).	23526464
RET M918T	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET M918T in culture (PMID: 23526464).	23526464
RET rearrange	papillary thyroid carcinoma	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) decreased proliferation of papillary thyroid carcinoma cells harboring the RET/PTC1 rearrangement in culture (PMID: 23526464).	23526464
RET S891A	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET S891A in culture (PMID: 23526464).	23526464
RET Y806C	Advanced Solid Tumor	sensitive	Ponatinib	Preclinical	Actionable	In a preclinical study, Iclusig (ponatinib) inhibited phosphorylation of Ret in transformed human cells expressing RET Y806C in culture (PMID: 23526464).	23526464

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