Division of Medical Oncology, University of Colorado Denver and University of Colorado Cancer Center, Denver, Colorado 80045, USA.
Clin Cancer Res. 2012 May 1;18(9):2704-14. doi: 10.1158/1078-0432.CCR-11-3167.
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.
磷酸肌醇 3-激酶 (PI3K) 和Src 信号通路的失调在结直肠癌中经常发生。PIK3CA 基因突变与疾病严重程度的增加和更差的临床结局相关。在癌前病变中已经鉴定出Src 的水平升高，并且被认为在肿瘤进展中起核心作用。由于这些途径似乎增强了肿瘤的生长和转移，目前正在早期临床试验中评估针对这两个途径的分子靶向药物。
我们使用结直肠癌细胞系和患者衍生的外植体模型来研究 saracatinib 的疗效。评估了 PIK3CA 中的突变，以研究 PIK3CA 基因突变与对 saracatinib 的敏感性之间的关联。
我们已经确定了一组具有 PIK3CA（外显子 9 和 20）突变的患者对 saracatinib 的敏感性增加。还发现了一种新的 3'非翻译区 (UTR) 突变与对 saracatinib 的敏感性增加相关，并且与 miR-520a 和 miR-525a 的亲和力降低有关。重要的是，我们表明 Src 抑制减少了 Src 和 p85 之间的相互作用，随后降低了 Akt 依赖性信号。
这些结果表明，针对结直肠癌中具有 PIK3CA 突变的患者的 Src 的个性化方法可能在具有这种遗传改变的一部分患者中有效。
