Ponatinib (AP24534) Is a Novel Potent Inhibitor of Oncogenic RET Mutants Associated With Thyroid Cancer

Context: 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. Objective: We tested whether ponatinib inhibited RET kinase and oncogenic activity. Methods: 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. Results: 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 o...