PIP5K1A Enhances Phosphoinositide Signaling to Drive Breast Cancer

项目总结 I类磷脂酰肌醇-3激酶α(PI3Kα)，产生信号转导的磷脂酰肌醇3，4，5- 三磷酸(PIP3)在超过40%的乳腺癌病例中过度活跃。最近的临床试验结果显示 结果表明，靶向抑制PI3Kα能有效延长这些患者的生存期。PI3K产生PIP3 通过磷脂酰肌醇合成的磷脂酰肌醇4，5-二磷酸(PIP2)的磷酸化 4-磷酸-5-激酶(PIP5Ks)。PIP5K1A被认为与乳腺癌有关，并被发现 在超过18%的肿瘤中扩增，尽管经常存在失活突变。这种扩增是独立的。 这些病例中有一半发生了PI3Kα突变。然而，目前还不清楚PIP5K1A的扩增是否 而PIP2水平的升高将通过增加PIP3的产生来推动肿瘤的生长。这一特殊事件的目标是 应用是为了确定PIP5K1A表达增加扰乱PIP2动态平衡的机制， 以及随后升高的PIP2水平如何驱动PI3K信号转导。中心假设是放大 PIP5K1A使负调控因子饱和，导致PIP2升高和PI3K信号增加，无论 PIP5K的催化活性。这项拟议研究的基本原理是，这将揭示PIP5K1A是如何放大的 在乳腺癌中驱动PI3K信号转导。在强劲的初步数据的指导下，这一假设将被用来检验 两个特定的目标：1)确定PIP2在质膜上的稳态机制；2)定义 PIP2稳态改变在驱动PI3K信号转导中的作用及其对乳腺癌细胞增殖的影响。在……下面 第一个目标，将确定PIP5K与负调节子之间的相互作用以及对 将确定其催化活性。在第二个目标下，PIP5K1A的过度表达和升高的作用 将测定PIP2水平对PI3K信号转导和乳腺癌细胞增殖的影响。拟议的研究是 这项研究意义重大，因为它将确定PIP5K1A是乳腺癌对PI3Kα抑制剂敏感性的新生物标记物。 这将是在不激活的情况下为约10%的乳腺癌病例建立治疗方案的关键第一步 PI3Kα。

PROJECT SUMMARY The class I phosphoinositide-3 kinase α (PI3Kα), which produces the signaling lipid phosphatidylinositol 3,4,5- trisphosphate (PIP3), is overactive in over 40% of breast cancer cases. Results from recent clinical trials have shown that targeted inhibition of PI3Kα is effective in prolonging survival in these patients. PI3Ks produce PIP3 by phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2), which is synthesized by phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks). PIP5K1A has been implicated as a driver in breast cancer and is found amplified in over 18% of tumors, though often with inactivating mutations. This amplification is found independent of PI3Kα mutations in half of these cases. However, it is not yet understood whether amplification of PIP5K1A and elevated PIP2 levels will drive tumor growth by increasing PIP3 production. The objective in this particular application is to determine the mechanism by which increased PIP5K1A expression disrupts PIP2 homeostasis, and how subsequently elevated PIP2 levels drive PI3K signaling. The central hypothesis is that amplification of PIP5K1A saturates a negative regulator, leading to elevated PIP2 and increased PI3K signaling, regardless of PIP5K catalytic activity. The rationale for the proposed research is that this will reveal how amplified PIP5K1A drives PI3K signaling in breast cancer. Guided by strong preliminary data, this hypothesis will be tested using two specific aims: 1) Identify the mechanism of PIP2 homeostasis at the plasma membrane; and 2) Define the role of altered PIP2 homeostasis in driving PI3K signaling, and its effects breast cancer cell proliferation. Under the first aim, the interaction between PIP5K and a negative regulator will be determined and the effects on catalytic activity will be identified. Under the second aim, the effect of PIP5K1A over-expression and elevated PIP2 levels on PI3K signaling and breast cancer cell proliferation will be determined. The proposed research is significant because it will identify PIP5K1A as a novel biomarker of breast cancer sensitivity to PI3Kα inhibitors. This will be a critical first step in establishing treatment options for ~10% of breast cancer cases without activation of PI3Kα.