Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients

Andrew P. Garner, Joseph M. Gozgit, Rana Anjum, Sadanand Vodala, Alexa Schrock, Tianjun Zhou, Cesar Serrano, Grant Eilers, Meijun Zhu, Julia Ketzer, Scott Wardwell, Yaoyu Ning, Youngchul Song, Anna Kohlmann, Frank Wang, Tim Clackson, Michael C. Heinrich, Jonathan A. Fletcher, Sebastian Bauer, Victor M. Rivera

    Research output: Contribution to journalArticle

    88 Scopus citations

    Abstract

    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 (30mgdaily) 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.

    Original languageEnglish (US)
    Pages (from-to)5745-5755
    Number of pages11
    JournalClinical Cancer Research
    Volume20
    Issue number22
    DOIs
    StatePublished - Nov 15 2014

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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    Garner, A. P., Gozgit, J. M., Anjum, R., Vodala, S., Schrock, A., Zhou, T., Serrano, C., Eilers, G., Zhu, M., Ketzer, J., Wardwell, S., Ning, Y., Song, Y., Kohlmann, A., Wang, F., Clackson, T., Heinrich, M. C., Fletcher, J. A., Bauer, S., & Rivera, V. M. (2014). Ponatinib inhibits polyclonal drug-resistant KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients. Clinical Cancer Research, 20(22), 5745-5755. https://doi.org/10.1158/1078-0432.CCR-14-1397