Garner Andrew P, Gozgit Joseph M, Anjum Rana, Vodala Sadanand, Schrock Alexa, Zhou Tianjun, Serrano Cesar, Eilers Grant, Zhu Meijun, Ketzer Julia, Wardwell Scott, Ning Yaoyu, Song Youngchul, Kohlmann Anna, Wang Frank, Clackson Tim, Heinrich Michael C, Fletcher Jonathan A, Bauer Sebastian, Rivera Victor M
ARIAD Pharmaceuticals, Inc, Cambridge, MA.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Clin Cancer Res. 2014 Nov 15;20(22):5745-5755. doi: 10.1158/1078-0432.CCR-14-1397. Epub 2014 Sep 19.
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.
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.
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.
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.
KIT是胃肠道间质瘤（GIST）的主要致癌驱动因子。伊马替尼、舒尼替尼和瑞戈非尼是已获批的治疗药物；然而，疗效常常受到KIT中多克隆继发性耐药突变的限制，其中位于激活（A）环（外显子17/18）的突变尤其成问题。在此，我们在临床前模型中探究了波纳替尼对KIT的抑制活性，并描述了其在GIST患者中的活性初步特征。
使用加速诱变试验以及一组工程改造和GIST来源的细胞系，评估了波纳替尼、伊马替尼、舒尼替尼和瑞戈非尼对突变型KIT的细胞活性和体内活性。还确定了波纳替尼 - KIT的共结构。在三名先前接受过所有三种FDA批准药物治疗的GIST患者中检测了波纳替尼的临床活性。
在工程改造和GIST来源的细胞系中，波纳替尼有效抑制KIT外显子11原发性突变体以及一系列继发性突变体，包括A环内的突变体。波纳替尼还在含有这些继发性突变的工程改造和GIST来源的肿瘤模型中诱导肿瘤消退。在诱变筛选中，40 nmol/L的波纳替尼足以抑制除V654A之外的所有继发性突变体的生长，V654A在80 nmol/L时被抑制。基于结构分析，这种抑制谱是合理的。波纳替尼（每日30 mg）在三名GIST患者中的两名中显示出令人鼓舞的临床活性。
波纳替尼对大多数主要临床相关的KIT突变体具有强大活性，并已在难治性GIST患者中证明了活性的初步证据。这些数据有力支持对GIST患者进一步评估波纳替尼。
