Sen Adrish, Khan Salmaan, Rossetti Stefano, Broege Aaron, MacNeil Ian, DeLaForest Ann, Molden Jhomary, Davis Laura, Iversrud Charles, Seibel Megan, Kopher Ross, Schulz Stephen, Laing Lance
Celcuity, Inc., Minneapolis, MN, USA.
Mol Oncol. 2025 Jan;19(1):225-247. doi: 10.1002/1878-0261.13703. Epub 2024 Aug 2.
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.
转移性去势抵抗性前列腺癌（mCRPC）的特征在于雄激素受体（AR）敏感性丧失以及PI3K/AKT/mTOR（PAM）通路的致癌激活。PI3K调节因子PTEN的缺失在前列腺癌（PC）的起始、进展和治疗抵抗过程中很常见。共同靶向PAM/AR通路是一种有前景的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。我们推测，gedatolisib是一种对所有I类PI3K亚型以及mTORC1和mTORC2均具有强效抑制作用的抑制剂，在PC细胞中比靶向单个PAM通路节点的抑制剂更有效。通过功能和代谢分析相结合的方法，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：everolimus）的敏感性。与其他PAM抑制剂相比，gedatolisib诱导的抗增殖和细胞毒性作用具有更高的效力和效果，且与PTEN/PIK3CA状态无关。gedatolisib的优越效果可能与更有效地抑制关键的PAM控制的细胞功能有关，包括细胞周期、存活、蛋白质合成、氧消耗率和糖酵解。我们的结果表明，对所有I类PI3K亚型、mTORC1和mTORC2进行强效且同时的阻断可以规避PTEN依赖性耐药。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均显示出有前景的初步疗效和安全性。Gedatolisib目前正在一项1/2期临床试验中与darolutamide联合用于先前接受过AR抑制剂治疗的mCRPC患者，以及在一项3期临床试验中与palbociclib和氟维司群联合用于HR+/HER2-晚期乳腺癌患者。
