Use of ponatinib to inhibit kinase mutations associated with drug-resistant gastrointestinal stromal tumors (GIST).

• DOI: 10.1200/jco.2013.31.15_suppl.10509
• Publication Date: 2020-03-11T15:44:51Z
• Authors: Michael C. Heinrich; Jonathan A. Fletcher; Rana Anjum; Cesar Serrano-Garcia; Sadanand Vodala; Sebastian Bauer; Ajia Town; Meijun Zhu; Yaoyu Ning; Grant Eilers; Diana Griffith; Janice Patterson; Arin McKinley; Frank Y Wang; Andrew P Garner; Victor M. Rivera
• Keywords: Ponatinib; Regorafenib; Imatinib Mesylate

10509 Background: Ponatinib (PO) is a multi-targeted tyrosine kinase inhibitor with potent pan-BCR-ABL activity that has recently been approved for treatment of CML and Ph + ALL. PO also inhibits the KIT. Approximately 80% gastrointestinal stromal tumors (GIST) contain primary activating KIT mutations, majority which cluster in exon 11. Imatinib (IM) 1 st line GIST; however, patients frequently relapse due to acquisition secondary resistance mutations located either ATP-binding pocket or activation (A) loop. Sunitinib (SU) 2 nd GIST but does not effectively inhibit A-loop mutants. Here we explored against major mutants found GIST. Methods: The drug sensitivity was determined using engineered Ba/F3 cells harboring mutant forms 11 without ATP binding mutations. abilities PO, IM, SU, regorafenib (RE) viability and/or were compared this system as well an isogenic CHO cell system. We profiled these same drugs panel lines, including lines IM-resistant Results: In all vitro systems, potently inhibited kinases, IC50 < 30 nM. range mutants, multiple kinases. induced substantial tumor regression models expressing mutation (D816H). Using those more than RE. Importantly, dosed once daily 45 mg ponatinib, plasma concentrations achieved are predicted lead inhibition tested possible exception V654A. Conclusions: clinically relevant kinases broader spectrum Based on data, phase study drug-resistant being initiated.