Common PIK3CA mutants and a novel 3' UTR mutation are associated with increased sensitivity to saracatinib.
Common PIK3CA mutants and a novel 3' UTR mutation are associated with increased sensitivity to saracatinib.
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DOI：
10.1158/1078-0432.ccr-11-3167
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发表时间：
2012-05-01
期刊：
影响因子：
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通讯作者：
Messersmith WA
中科院分区：
文献类型：
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作者：
Arcaroli JJ;Quackenbush KS;Powell RW;Pitts TM;Spreafico A;Varella-Garcia M;Bemis L;Tan AC;Reinemann JM;Touban BM;Dasari A;Eckhardt SG;Messersmith WA
磷酸肌醇3-激酶（PI 3 K）和Src信号通路的失调通常发生在结直肠癌中。PIK 3CA基因突变与疾病严重程度增加和临床结局恶化相关。Src水平升高已在癌前病变中被确定，并被认为在肿瘤进展中起核心作用。由于这些途径似乎会增强肿瘤的生长和转移，因此目前正在早期临床试验中评估这两种途径的分子靶向药物。我们使用结直肠癌细胞系和患者来源的外植体模型来研究saracatinib的疗效。评价PIK 3CA中的突变，以检查PIK 3CA基因突变与对saracatinib敏感性之间的相关性。我们已经确定了一个PIK 3CA（外显子9和20）突变的患者子集，对saracatinib的敏感性增加。一种新的3′非翻译区（UTR）突变也显示与对saracatinib的敏感性增加相关，并且对miR-520 a和miR-525 a的亲和力降低。重要的是，我们发现Src抑制减少了Src和p85之间的相互作用，随后减少Akt依赖性信号传导。这些结果表明，在患有结直肠癌的PIK 3CA突变患者中靶向Src的个性化方法可能证明在具有这种遗传改变的患者亚组中有效。
Dysregulation of the phosphoinositide 3-kinase (PI3K) and Src signaling pathways commonly occur in colorectal cancer. Mutations in the PIK3CA gene are associated with an increase in severity of disease and worse clinical outcomes. Elevated levels of Src have been identified in premalignant lesions and are suggested to play a central role in tumor progression. Because these pathways appear to enhance tumor growth and metastasis, molecularly targeted agents for both pathways are currently being evaluated in early-phase clinical trials. We used colorectal cancer cell lines and a patient-derived explant model to investigate the efficacy of saracatinib. Mutations in the PIK3CA were evaluated to examine the association between mutations in the PIK3CA gene and sensitivity to saracatinib. We have identified a subset of patients with a PIK3CA (exon 9 and 20) mutation with increased sensitivity to saracatinib. A novel 3′ untranslated region (UTR) mutation was also shown to be associated with increased sensitivity to saracatinib and have a reduced affinity for miR-520a and miR-525a. Importantly, we show that Src inhibition reduces the interaction between Src and p85, subsequently decreasing Akt-dependent signaling. These results indicate that a personalized approach in targeting Src in PIK3CA-mutant patients with colorectal cancers may prove effective in a subset of patients with this genetic alteration.