Platt Fiona M, Hurst Carolyn D, Taylor Claire F, Gregory Walter M, Harnden Patricia, Knowles Margaret A
Cancer Research UK Clinical Centre, Leeds Institute of Molecular Medicine, United Kingdom.
Clin Cancer Res. 2009 Oct 1;15(19):6008-17. doi: 10.1158/1078-0432.CCR-09-0898. Epub 2009 Sep 29.
The phosphatidylinositol 3-kinase (PI3K) pathway can be activated by alterations affecting several pathway components. For rational application of targeted therapies, detailed understanding of tumor biology and approaches to predict efficacy in individual tumors are required. Our aim was to assess the frequency and distribution of pathway alterations in bladder cancer.
We examined the pathway components (PIK3CA, PTEN, TSC1, RHEB, and LKB1) and putative upstream regulators (FGFR3 and RAS genes) for mutation, allelic loss, copy number alteration, and expression in bladder tumors and cell lines.
No mutations were found in RHEB and only a single mutation in LKB1. PIK3CA mutations were detected in 25% of tumors and 26% of cell lines with a significant excess of helical domain mutations (E542K and E545K). There was over-representation but not amplification of the gene. Loss of heterozygosity of the PTEN region and homozygous deletion were found in 12% and 1.4% of tumors, and reduced expression in 49%. Forty-six percent of cell lines showed alterations that implicated PTEN. Sixteen percent of tumors and 11% of cell lines showed TSC1 mutation, and 9q loss of heterozygosity was common (57%). Pathway alterations were independently distributed, suggesting that the mutation of two pathway members may have additive or synergistic effects through noncanonical functions.
PI3K pathway alterations are common in bladder cancer. The lack of redundancy of alterations suggests that single-agent PI3K-targeted therapy may not be successful in these cancers. This study provides a well-characterized series of cell lines for use in preclinical studies of targeted agents.
磷脂酰肌醇3-激酶（PI3K）通路可因影响多个通路组分的改变而被激活。为了合理应用靶向治疗，需要深入了解肿瘤生物学以及预测个体肿瘤疗效的方法。我们的目的是评估膀胱癌中通路改变的频率和分布。
我们检测了膀胱癌肿瘤组织和细胞系中通路组分（PIK3CA、PTEN、TSC1、RHEB和LKB1）以及假定的上游调节因子（FGFR3和RAS基因）的突变、等位基因缺失、拷贝数改变和表达情况。
在RHEB中未发现突变，LKB1仅发现一个突变。在25%的肿瘤组织和26%的细胞系中检测到PIK3CA突变，其中螺旋结构域突变（E542K和E545K）明显过量。该基因存在过表达但无扩增。在12%的肿瘤组织中发现PTEN区域杂合性缺失，1.4%的肿瘤组织存在纯合缺失，49%的肿瘤组织PTEN表达降低。46%的细胞系显示与PTEN相关的改变。16%的肿瘤组织和11%的细胞系显示TSC1突变，9号染色体杂合性缺失很常见（57%）。通路改变是独立分布的，这表明两个通路成员的突变可能通过非经典功能产生累加或协同效应。
PI3K通路改变在膀胱癌中很常见。改变缺乏冗余性表明，单药PI3K靶向治疗在这些癌症中可能不会成功。本研究提供了一系列特征明确的细胞系，可用于靶向药物的临床前研究。
