转移性去势抵抗性前列腺癌 (mCRPC) 的特点是雄激素受体 (AR) 敏感性丧失和 PI3K/AKT/mTOR (PAM) 通路致癌激活。 PI3K 调节因子 PTEN 的缺失在前列腺癌 (PC) 发生、进展和治疗耐药期间很常见。共同靶向 PAM/AR 通路是一种很有前景的 mCRPC 治疗策略，但受到相互负反馈抑制或反馈缓解的阻碍。大多数 PAM 抑制剂选择性地保留（或弱抑制）PAM 通路的一个或多个关键节点，根据患者的 PAM 通路突变状态增强耐药性。我们假设 gedatolisib 是所有 I 类 PI3K 同工型以及 mTORC1 和 mTORC2 的均效抑制剂，比针对 PC 细胞中单个 PAM 通路节点的抑制剂更有效。通过结合功能和代谢测定，我们评估了一组具有不同 PTEN/PIK3CA 状态的 PC 细胞系对多节点 PAM 抑制剂（PI3K/mTOR：gedatolisib、samotolisib）和单节点 PAM 抑制剂（PI3Kα： alpelisib；AKT：capivasertib；mTOR：依维莫司）。相对于其他 PAM 抑制剂，Gedatolisib 诱导抗增殖和细胞毒性作用，具有更大的效力和功效，且与 PTEN/PIK3CA 状态无关。 gedatolisib 的卓越效果可能与更有效地抑制 PAM 控制的关键细胞功能有关，包括细胞周期、存活、蛋白质合成、耗氧率和糖酵解。我们的结果表明，有效且同时阻断所有 I 类 PI3K 同工型、mTORC1 和 mTORC2 可以规避 PTEN 依赖性耐药性。 Gedatolisib 作为单一药物以及与其他疗法联合使用，在各种实体瘤类型中报告了有希望的初步疗效和安全性。目前正在一项 1/2 期临床试验中评估 Gedatolisib 与 darolutamide 联合治疗既往接受过 AR 抑制剂治疗的 mCRPC 患者，并在一项 3 期临床试验中与 Palbociclib 和氟维司群联合治疗 HR /HER2-晚期乳腺癌患者癌症。© 2024 作者。约翰·威利出版的《分子肿瘤学》

Metastatic castration-resistant prostate cancer (mCRPC) is characterized by loss of androgen receptor (AR) sensitivity and oncogenic activation of the PI3K/AKT/mTOR (PAM) pathway. Loss of the PI3K regulator PTEN is frequent during prostate cancer (PC) initiation, progression, and therapeutic resistance. Co-targeting the PAM/AR pathways is a promising mCRPC treatment strategy but is hampered by reciprocal negative feedback inhibition or feedback relief. Most PAM inhibitors selectively spare (or weakly inhibit) one or more key nodes of the PAM pathway, potentiating drug resistance depending on the PAM pathway mutation status of patients. We posited that gedatolisib, a uniformly potent inhibitor of all class I PI3K isoforms, as well as mTORC1 and mTORC2, would be more effective than inhibitors targeting single PAM pathway nodes in PC cells. Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi-node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single-node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib induced anti-proliferative and cytotoxic effects with greater potency and efficacy relative to the other PAM inhibitors, independent of PTEN/PIK3CA status. The superior effects of gedatolisib were likely associated with more effective inhibition of critical PAM-controlled cell functions, including cell cycle, survival, protein synthesis, oxygen consumption rate, and glycolysis. Our results indicate that potent and simultaneous blockade of all class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN-dependent resistance. Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2- advanced breast cancer.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.