van de Stolpe Anja
Precision Diagnostics, Philips Research, High Tech Campus, 5656AE Eindhoven, The Netherlands.
Cancers (Basel). 2019 Mar 1;11(3):293. doi: 10.3390/cancers11030293.
The phosphoinositide 3-kinase (PI3K) growth factor signaling pathway plays an important role in embryonic development and in many physiological processes, for example the generation of an immune response. The pathway is frequently activated in cancer, driving cell division and influencing the activity of other signaling pathways, such as the MAPK, JAK-STAT and TGFβ pathways, to enhance tumor growth, metastasis, and therapy resistance. Drugs that inhibit the pathway at various locations, e.g., receptor tyrosine kinase (RTK), PI3K, AKT and mTOR inhibitors, are clinically available. To predict drug response versus resistance, tests that measure PI3K pathway activity in a patient sample, preferably in combination with measuring the activity of other signaling pathways to identify potential resistance pathways, are needed. However, tests for signaling pathway activity are lacking, hampering optimal clinical application of these drugs. We recently reported the development and biological validation of a test that provides a quantitative PI3K pathway activity score for individual cell and tissue samples across cancer types, based on measuring Forkhead Box O (FOXO) transcription factor target gene mRNA levels in combination with a Bayesian computational interpretation model. A similar approach has been used to develop tests for other signaling pathways (e.g., estrogen and androgen receptor, Hedgehog, TGFβ, Wnt and NFκB pathways). The potential utility of the test is discussed, e.g., to predict response and resistance to targeted drugs, immunotherapy, radiation and chemotherapy, as well as (pre-) clinical research and drug development.
磷酸肌醇-3激酶（PI3K）生长因子信号通路在胚胎发育和许多生理过程中发挥着重要作用，例如免疫反应的产生。该通路在癌症中经常被激活，驱动细胞分裂并影响其他信号通路的活性，如MAPK、JAK-STAT和TGFβ通路，从而促进肿瘤生长、转移和治疗耐药性。临床上已有在不同位点抑制该通路的药物，例如受体酪氨酸激酶（RTK）、PI3K、AKT和mTOR抑制剂。为了预测药物反应与耐药性，需要进行检测以测量患者样本中的PI3K通路活性，最好是结合测量其他信号通路的活性以识别潜在的耐药通路。然而，目前缺乏信号通路活性检测方法，这阻碍了这些药物的最佳临床应用。我们最近报道了一种检测方法的开发和生物学验证，该方法基于测量叉头框O（FOXO）转录因子靶基因mRNA水平，并结合贝叶斯计算解释模型，为跨癌症类型的个体细胞和组织样本提供定量的PI3K通路活性评分。类似的方法已被用于开发其他信号通路的检测方法（例如，雌激素和雄激素受体、刺猬信号、TGFβ、Wnt和NFκB通路）。本文讨论了该检测方法的潜在用途，例如预测对靶向药物、免疫疗法、放疗和化疗的反应和耐药性，以及（临床前）临床研究和药物开发。
