Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Harvard Medical School, Boston, Massachusetts, USA.
Prostate. 2022 Aug;82 Suppl 1:S60-S72. doi: 10.1002/pros.24372.
Despite significant advances in molecular characterization and therapeutic targeting of advanced prostate cancer, it remains the second most common cause of cancer death in men in the United States. The PI3K (Phosphatidylinositol 3-kinase)/AKT (AKT serine/threonine kinase)/mTOR (mammalian target of rapamycin) signaling pathway is commonly altered in prostate cancer, most frequently through loss of the PTEN (Phosphatase and Tensin Homolog) tumor suppressor, and is critical for cancer cell proliferation, migration, and survival.
This study summarizes signaling through the PTEN/PI3K pathway, alterations in pathway components commonly seen in advanced prostate cancer, and results of clinical trials of pathway inhibitors reported to date with a focus on more recently reported studies. It also reviews rationale for combination approaches currently under study, including with taxanes, immune checkpoint inhibitors and poly (ADP-ribose) polymerase inhibitors, and discusses future directions in biomarker testing and therapeutic targeting of this pathway.
Clinical trials studying pharmacologic inhibitors of PI3K, AKT or mTOR kinases have demonstrated modest activity of specific agents, with several trials of pathway inhibitors currently in progress. A key challenge is the importance of PI3K/AKT/mTOR signaling in noncancerous tissues, leading to predictable but often severe toxicities at therapeutic doses.
Further advances in selective pharmacologic inhibition of the PI3K/AKT/mTOR pathway in tumors, development of rational combinations, and appropriate biomarker selection to identify the appropriate tumor- and patient-specific vulnerabilities will be required to optimize clinical benefit from therapeutic targeting of this pathway.
尽管在分子特征描述和晚期前列腺癌的靶向治疗方面取得了重大进展，但在美国，前列腺癌仍是男性癌症死亡的第二大常见原因。PI3K（磷脂酰肌醇 3-激酶）/AKT（AKT 丝氨酸/苏氨酸激酶）/mTOR（雷帕霉素哺乳动物靶标）信号通路在前列腺癌中经常发生改变，最常见的是通过抑癌基因 PTEN（磷酸酶和张力蛋白同源物）的缺失，对癌细胞的增殖、迁移和存活至关重要。
本研究总结了 PTEN/PI3K 通路的信号转导、晚期前列腺癌中常见的通路成分改变，以及迄今为止报告的通路抑制剂临床试验结果，重点介绍了最近报告的研究。它还回顾了目前正在研究的联合治疗方法的原理，包括与紫杉烷类、免疫检查点抑制剂和聚（ADP-核糖）聚合酶抑制剂的联合，讨论了该途径生物标志物检测和治疗靶向的未来方向。
研究 PI3K、AKT 或 mTOR 激酶的药理学抑制剂的临床试验表明，特定药物的活性中等，目前正在进行几项通路抑制剂试验。一个关键的挑战是 PI3K/AKT/mTOR 信号在非癌细胞组织中的重要性，导致在治疗剂量下出现可预测但通常严重的毒性。
需要进一步推进肿瘤中 PI3K/AKT/mTOR 通路的选择性药理学抑制，开发合理的联合治疗方法，并选择适当的生物标志物来识别适当的肿瘤和患者特异性脆弱性，以优化该通路治疗靶向的临床获益。
