Purpose

The PI3K/AKT/mTOR pathway is one of the most highly activated cellular signaling pathways in advanced ovarian cancer. Although several PI3K/AKT/mTOR inhibitors have been developed to treat various types of cancer, the antitumor efficacy of many of these compounds against ovarian cancer has remained unclear.

Methods

Here, we tested and compared a panel of 16 PI3K/AKT/mTOR inhibitors (XL765, Miltefosine, Rapamycin, CCI-779, RAD001, FK506, XL147, GSK2110183, IPI-145, GSK2141795, BYL719, GSK458, CAL-101, XL765 analogue SAR245409, Triciribine, and GDC0941) that have entered clinical trials for antitumor activity against ovarian cancer, as well as the front line drug, paclitaxel. Antitumor efficacy was measured in both ovarian cancer cell lines and patient-derived ovarian primary tumor cell lines in vitro and in vivo.

Results

We identified the PI3K/mTOR dual inhibitor GSK458 as a potent inhibitor of proliferation in all cell lines tested at half maximal inhibitory concentrations (IC₅₀) of approximately 0.01-1 µM, a range tens to hundreds fold lower than that of the other PI3K/AKT/mTOR inhibitors tested. Additionally, GSK458 showed the highest inhibitory efficacy against ovarian cancer cell migration. GSK458 also inhibited tumor growth and metastasis in nude mice intraperitoneally engrafted with SKOV3 cells or a patient-derived tumor cell xenograft (PDCX). Importantly, the inhibitory efficiency of GSK458 on cell proliferation and migration both in vitro and in vivo was comparable to that of paclitaxel. Mechanistically, the anti-tumor activity of GSK458 was found to be associated with inactivation of AKT and mTOR, and induction of cell cycle arrest at the G0/G1 phase.

Conclusions

Based on our results, we conclude that GSK458 may serve as an attractive candidate to treat ovarian cancer.

中文翻译：

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PI3K / mTOR双重抑制剂GSK458可有效阻止卵巢癌的肿瘤发生和转移。

目的

PI3K / AKT / mTOR途径是晚期卵巢癌中激活程度最高的细胞信号传导途径之一。尽管已开发出几种PI3K / AKT / mTOR抑制剂来治疗各种类型的癌症，但许多此类化合物对卵巢癌的抗肿瘤功效仍不清楚。

方法

在这里，我们测试并比较了16种PI3K / AKT / mTOR抑制剂（XL765，米替福辛，雷帕霉素，CCI-779，RAD001，FK506，XL147，GSK2110183，IPI-145，GSK2141795，BYL719，GSK458，CAL-101，XL765类似物SAR245409，Triciribine和GDC0941）已进入临床试验，以抗卵巢癌的抗肿瘤活性，以及​​前线药物紫杉醇。在体外和体内，在卵巢癌细胞系和患者来源的卵巢原发性肿瘤细胞系中均测量了抗肿瘤功效。

结果

我们将PI3K / mTOR双重抑制剂GSK458确定为在所有最大抑制浓度（IC ₅₀）约为0.01-1 µM的一半的测试细胞系中的有效增殖抑制剂，其范围比其他PI3K / m3低数十至数百倍测试了AKT / mTOR抑制剂。此外，GSK458对卵巢癌细胞的迁移表现出最高的抑制作用。GSK458还抑制了腹膜内植入SKOV3细胞或患者源性肿瘤细胞异种移植物（PDCX）的裸鼠的肿瘤生长和转移。重要的是，GSK458在体外和体内对细胞增殖和迁移的抑制效率与紫杉醇相当。从机理上讲，发现GSK458的抗肿瘤活性与AKT和mTOR的失活以及诱导细胞周期阻滞在G0 / G1期有关。

结论

根据我们的结果，我们得出结论，GSK458可以作为治疗卵巢癌的有吸引力的候选药物。