Sunitinib (SU) response in imatinib-resistant (IM-R) GIST correlates with KIT and PDGFRA mutation status.
Sunitinib (SU) response in imatinib-resistant (IM-R) GIST correlates with KIT and PDGFRA mutation status.
复制标题
舒尼替尼 (SU) 在伊马替尼耐药 (IM-R) GIST 中的反应与 KIT 和 PDGFRA 突变状态相关。
DOI：
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发表时间：
2006
影响因子：
45.3
通讯作者：
G. Demetri
中科院分区：
文献类型：
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作者：
M. Heinrich;Robert G. Maki;C. L. Corless;C. Antonescu;Jonathan A Fletcher;C. D. Fletcher;Xuelin Huang;Charles M. Baum;G. Demetri
背景：IM抵抗在晚期GIST中是一个主要的临床问题。SU(SU11248)是一种口服多靶点酪氨酸激酶抑制剂，具有与KIT、PDGFRs、VEGFRs、RET和Flt3抑制相关的抗肿瘤和抗血管生成活性。SU已在IM-R GIST患者的临床试验中证明了疗效。
方法
作为I/II期试验的一部分，这项研究调查了97例转移性IM-R GIST患者的肿瘤激酶基因型别与SU临床活动性之间的关系。肿瘤通过CT或MRI进行成像，以进行RECIST定义的反应评估。肿瘤标本分别在注射前(n=76)和注射后(n=)获得，并分别分析原发或继发KIT和PDGFRA突变。
结果
临床受益(定义为PR或SD>；6个月)所有主要分子GIST亚型：KIT外显子11(42例，CB 36%)、KIT外显子9(19例，CB 42%)、PDGFRA(4例，CB 25%)、无KIT或PDGFRA突变(野生型[WT]；9例，CB 56%)。值得注意的是，具有原发KIT外显子9突变的医师的PR率为37%，而KIT外显子11突变的PR率为5%(P=0.003)。KIT外显子9突变和WT KIT/PDGFRA突变的PFS和OS明显长于KIT外显子11突变的PFS和OS(外显子9 vs 11：PFS P=0.0007，OS P=0.005；WT vs外显子11：PFS P=0.03，OS P=0.005)。原发KIT外显子11突变的GIST中有62%发生继发性KIT突变(外显子13、14、17或18)，而原发KIT外显子9突变的GIST中仅有16%发生继发性KIT突变(P=0.002)。在缺乏KIT/PDGFRA原发突变的GIST中未发现继发突变。生化图谱显示KIT外显子13和14突变对SU敏感，KIT外显子17和18突变对SU耐药。这些体外结果与临床结果一致：在继发KIT外显子13或14突变的患者中，65%的患者出现CB，而在继发KIT外显子17或18突变的患者中，仅有9%的患者出现CB(P=0.006)。
结论
我们的发现表明，与先前使用伊马替尼观察到的结果类似，IM治疗失败后SU的CB明显受到主要致病激酶的初级和继发性突变的影响，其活性不受控制是GIST的关键病因因素。[表：见正文]。
9502 Background: IM resistance in advanced GIST represents a major clinical problem. SU (SU11248) is an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities related to KIT, PDGFRs, VEGFRs, RET and FLT3 inhibition. SU has demonstrated efficacy in clinical trials of pts with IM-R GIST.
METHODS
This study examined the relationship between tumor kinase genotypes and SU clinical activity in 97 pts with metastatic IM-R GIST treated as part of a phase I/II trial. Tumors were imaged by CT or MRI for RECIST-defined response assessment. Tumor specimens were obtained prior to (n=76) and following (n=64) IM therapy and analyzed for primary or secondary KIT and PDGFRA mutations, respectively.
RESULTS
Clinical benefit (CB; defined as PR or SD >6 months) with SU was observed for all major molecular GIST subtypes: KIT exon 11 (42 pts, CB 36%), KIT exon 9 (19 pts, CB 42%), PDGFRA (4 pts, CB 25%), no KIT or PDGFRA mutation (wild-type [WT]; 9 pts, CB 56%). Notably, the PR rate for GISTS with primary KIT exon 9 mutations was 37%, vs 5% for KIT exon 11 mutations (P=0.003). PFS and OS were significantly longer for pts with either a primary KIT exon 9 mutation or WT KIT/PDGFRA compared with pts with a KIT exon 11 mutation (exon 9 vs 11: PFS P=0.0007, OS P=0.005; WT vs exon 11: PFS P=0.03, OS P=0.01). Secondary KIT mutations (in exons 13, 14, 17 or 18) were found in 62% of GISTs with a primary KIT exon 11 mutation, but only in 16% with a primary KIT exon 9 mutation (P=0.002). No secondary mutations were found in GISTs lacking a primary KIT/PDGFRA mutation. Biochemical profiling of secondary kinase mutations revealed in-vitro sensitivity of KIT exon 13 and 14 mutations to SU, while secondary KIT exon 17 and 18 mutations were resistant to SU in vitro. These in-vitro results were consistent with clinical results: CB was observed in 65% of pts with secondary KIT mutations in exon 13 or 14 and in only 9% of pts with secondary KIT exon 17 or 18 mutations (P=0.006).
CONCLUSIONS
Our findings suggest that, similar to prior results observed using imatinib, CB of SU following failure of IM treatment is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinase, the uncontrolled activity of which is a critical etiologic factor for GIST. [Table: see text].