Non-Canonical Phosphatidylinositol Kinases in Triple Negative Breast Cancer

项目总结 三阴性乳腺癌(TNBC)占所有乳腺癌的15%-20%。患有TNBC的女性是三岁 与其他亚型相比，死亡的可能性要高出一倍。TNBC的预后不良可以归因于 缺乏有效的靶向治疗。尽管在TNBC中经常发现TP53突变，但很难 用药物靶向P53缺乏症。我们已经确定了一个非规范的磷脂酰肌醇激酶家族，即 磷脂酰肌醇-5-磷酸4-激酶(PI5P4Ks)及其在TP53肿瘤生长中的关键作用 像差。此外，我们发现了PI5P4K在自噬中的作用，并首次表明 这些酶定位于溶酶体，提示PI5P4K可能对溶酶体功能重要，如 揭示了PI5P4K抑制P53突变癌的抗癌机制。使用临床前研究 新型基因工程小鼠乳腺肿瘤模型、人乳腺癌细胞系和患者的研究 我们建议对乳腺肿瘤样本进行研究，以了解这些“可用药”的功能的生化基础 酵素。我们还将验证它们作为药物干预人类癌症的靶点，特别是对 靶向治疗未获成功的TNBC。我们的主要假设是PI5P4K 作为代谢压力的传感器，允许细胞调节溶酶体事件，包括自噬，以便 维持细胞动态平衡。此外，我们假设与P53突变相关的代谢重排， 为TNBC细胞的生长和存活创造了对PI5P4K的新的依赖。 在目标1中，我们将确定PI5P4K成为必不可少的合成脆弱性的机制 当P53缺陷时，肿瘤细胞生长。为此，我们将描述突变型p53是如何失去功能的 和功能的获得，有助于合成致命性以及解剖的代谢后果 P53突变型TNBC细胞中PI5P4K缺失。 在目标2中，我们将测试靶向PI5P4K在TNBC中的治疗效果 基因工程小鼠乳腺肿瘤模型和患者乳腺肿瘤样本。 这个项目的最终目标和总体影响是将PI5P4K表征为一种新的肿瘤易感性 以确定对患有这些疾病的TNBC患者进行治疗干预的机会 突变，目前缺乏有针对性的治疗。

PROJECT SUMMARY Triple negative breast cancer (TNBC) accounts for 15–20% of all breast cancers. Women with TNBC are three times more likely to experience death compared to other subtypes. The poor prognosis of TNBC can be attributed to the lack of effective targeted therapy. Although TP53 mutations are frequently found in TNBC, it is difficult to target p53-deficiency with drugs. We have identified a family of non-canonical phosphatidylinositol kinases, the phosphatidylinositol-5-phosphate 4-kinases (PI5P4Ks) and their crucial role in the growth of cancers with TP53 aberrations. Furthermore, we discovered a role for the PI5P4Ks in autophagy, and for the first time, showed that these enzymes localize to lysosomes, suggesting that the PI5P4Ks may be important for lysosome function, as well as shedding light on the anti-cancer mechanism of PI5P4K inhibition in p53 mutant cancers. Using preclinical studies in novel genetically engineered mouse breast tumor models, human breast cancer cell lines, and patient breast tumor samples we propose to investigate the biochemical basis for the function of these ‘druggable’ enzymes. We will also validate them as targets for pharmaceutical intervention in human cancers, especially for TNBC where targeted therapies have not been successful. Our overarching hypothesis is that the PI5P4Ks act as sensors of metabolic stress that allow cells to modulate lysosomal events, including autophagy, in order to maintain cellular homeostasis. Further, we posit that the metabolic rewiring associated with p53 mutations, create a novel dependency on the PI5P4Ks for TNBC cell growth and survival. In Aim 1 we will determine the mechanism of synthetic vulnerability by which the PI5P4Ks become essential for tumor cell growth when p53 is defective. To this end we will characterize how mutant p53, both loss of function and gain of function, contributes to the synthetic lethality as well as dissect the metabolic consequences of PI5P4K loss in p53 mutant TNBC cells. In Aim 2 we will test the therapeutic effectiveness of targeting the PI5P4Ks in TNBC using our genetically engineered mouse breast tumor models and patient breast tumor samples. The ultimate goal and the overall impact of this project are to characterize PI5P4Ks as a novel liability for tumors with TP53 mutations in order to define opportunities for therapeutic intervention for TNBC patients with these mutations, which currently lack targeted therapy.