PT  - JOURNAL ARTICLE
AU  - Garner, Andrew P.
AU  - Gozgit, Joseph M.
AU  - Anjum, Rana
AU  - Vodala, Sadanand
AU  - Schrock, Alexa
AU  - Zhou, Tianjun
AU  - Serrano, Cesar
AU  - Eilers, Grant
AU  - Zhu, Meijun
AU  - Ketzer, Julia
AU  - Wardwell, Scott
AU  - Ning, Yaoyu
AU  - Song, Youngchul
AU  - Kohlmann, Anna
AU  - Wang, Frank
AU  - Clackson, Tim
AU  - Heinrich, Michael C.
AU  - Fletcher, Jonathan A.
AU  - Bauer, Sebastian
AU  - Rivera, Victor M.
TI  - Ponatinib Inhibits Polyclonal Drug-Resistant KIT Oncoproteins and Shows Therapeutic Potential in Heavily Pretreated Gastrointestinal Stromal Tumor (GIST) Patients
AID  - 10.1158/1078-0432.CCR-14-1397
DP  - 2014 Nov 15
TA  - Clinical Cancer Research
PG  - 5745--5755
VI  - 20
IP  - 22
4099  - http://clincancerres.aacrjournals.org/content/20/22/5745.short
4100  - http://clincancerres.aacrjournals.org/content/20/22/5745.full
SO  - Clin Cancer Res2014 Nov 15; 20
AB  - Purpose: KIT is the major oncogenic driver of gastrointestinal stromal tumors (GIST). Imatinib, sunitinib, and regorafenib are approved therapies; however, efficacy is often limited by the acquisition of polyclonal secondary resistance mutations in KIT, with those located in the activation (A) loop (exons 17/18) being particularly problematic. Here, we explore the KIT-inhibitory activity of ponatinib in preclinical models and describe initial characterization of its activity in patients with GIST. Experimental Design: The cellular and in vivo activities of ponatinib, imatinib, sunitinib, and regorafenib against mutant KIT were evaluated using an accelerated mutagenesis assay and a panel of engineered and GIST-derived cell lines. The ponatinib–KIT costructure was also determined. The clinical activity of ponatinib was examined in three patients with GIST previously treated with all three FDA-approved agents. Results: In engineered and GIST-derived cell lines, ponatinib potently inhibited KIT exon 11 primary mutants and a range of secondary mutants, including those within the A-loop. Ponatinib also induced regression in engineered and GIST-derived tumor models containing these secondary mutations. In a mutagenesis screen, 40 nmol/L ponatinib was sufficient to suppress outgrowth of all secondary mutants except V654A, which was suppressed at 80 nmol/L. This inhibitory profile could be rationalized on the basis of structural analyses. Ponatinib (30 mg daily) displayed encouraging clinical activity in two of three patients with GIST. Conclusion:Ponatinib possesses potent activity against most major clinically relevant KIT mutants and has demonstrated preliminary evidence of activity in patients with refractory GIST. These data strongly support further evaluation of ponatinib in patients with GIST. Clin Cancer Res; 20(22); 5745–55. ©2014 AACR.