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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
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Drug Name Trade Name Synonyms Drug Classes Drug Description
Ponatinib Iclusig AP24534 ABL Inhibitor (pan) 9 BCR-ABL Inhibitor 31 DDR1 Inhibitor 10 DDR2 inhibitor 7 FGFR Inhibitor (Pan) 26 FLT3 Inhibitor 66 KIT Inhibitor 57 PDGFR-alpha Inhibitor 9 RET Inhibitor 52 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).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
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 2024).
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 similar cell proliferation and transformation activity to wild-type Ret in cell culture (PMID: 21810974, PMID: 32546069), and therefore, its effect on Ret protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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 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 rearrange thyroid gland papillary 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 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 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
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 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 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 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 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 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