The mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways are involved in cancer growth and survival; however, the clinical efficacy of single inhibitors of each pathway is limited or transient owing to resistance mechanisms, such as feedback signaling and/or re-expression of receptor-type tyrosine kinases (RTKs). This study identified a potent and novel kinase inhibitor, TAS0612, and characterized its properties. We found that TAS0612 is a potent, orally available compound that can inhibit p90RSK (RSK), AKT, and p70S6K (S6K) as a single agent and showed a strong correlation with the growth inhibition of cancer cells with PTEN loss or mutations, regardless of the presence of KRAS and BRAF mutations. Additional RSK inhibitory activity may differentiate the sensitivity profile of TAS0612 from that of signaling inhibitors that target only the PI3K pathway. Moreover, TAS0612 demonstrated broad-spectrum activity against tumor models wherein inhibition of MAPK or PI3K pathways was insufficient to exert antitumor effects. TAS0612 exhibited a stronger growth-inhibitory activity against the cancer cell lines and tumor models with dysregulated signaling with the genetic abnormalities described above than treatment with inhibitors against AKT, PI3K, MEK, BRAF, and EGFR/HER2. Additionally, TAS0612 demonstrated the persistence of blockade of downstream growth and anti-apoptotic signals, despite activation of upstream effectors in the signaling pathway and FoxO-dependent re-expression of HER3. In conclusion, TAS0612 with RSK/AKT/S6K inhibitory activity may provide a novel therapeutic strategy for cancer patients to improve clinical responses and overcome resistance mechanisms.

中文翻译：

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TAS0612 是一种新型 RSK、AKT 和 S6K 抑制剂，在临床前肿瘤模型中表现出抗肿瘤作用

丝裂原激活蛋白激酶 (MAPK) 和磷脂酰肌醇 3 激酶 (PI3K) 通路参与癌症的生长和存活；然而，由于耐药机制，例如反馈信号和/或受体型酪氨酸激酶（RTK）的重新表达，每个途径的单一抑制剂的临床疗效是有限或短暂的。这项研究鉴定了一种有效的新型激酶抑制剂 TAS0612，并表征了其特性。我们发现 TAS0612 是一种有效的口服化合物，作为单一药物可以抑制 p90RSK (RSK)、AKT 和 p70S6K (S6K)，并且与 PTEN 缺失或突变的癌细胞的生长抑制具有很强的相关性，无论KRAS 和 BRAF 突变的存在。额外的 RSK 抑制活性可能会使 TAS0612 的敏感性特征与仅针对 PI3K 通路的信号抑制剂的敏感性特征不同。此外，TAS0612 表现出针对肿瘤模型的广谱活性，其中 MAPK 或 PI3K 途径的抑制不足以发挥抗肿瘤作用。与使用针对 AKT、PI3K、MEK、BRAF 和 EGFR/HER2 的抑制剂治疗相比，TAS0612 对具有上述遗传异常的信号传导失调的癌细胞系和肿瘤模型表现出更强的生长抑制活性。此外，尽管信号通路中的上游效应器被激活并且 HER3 依赖于 FoxO 重新表达，但 TAS0612 仍表现出对下游生长和抗凋亡信号的持续阻断。总之，具有RSK/AKT/S6K抑制活性的TAS0612可能为癌症患者提供一种新的治疗策略，以改善临床反应并克服耐药机制。