Graduate Institute of Biomedical Sciences, Taiwan; Department of Physiology and Pharmacology, Taiwan; Molecular Medicine Research Center, Taiwan; Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei, Taiwan.
Molecular Medicine Research Center, Taiwan.
Biochem Pharmacol. 2020 Oct;180:114137. doi: 10.1016/j.bcp.2020.114137. Epub 2020 Jul 4.
LY3023414 (samotolisib) is a promising new dual inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR). Currently, multiple clinical trials are underway to evaluate the efficacy of LY3023414 in patients with various types of cancer. However, the potential mechanisms underlying acquired resistance to LY3023414 in human cancer cells still remain elusive. In this study, we investigated whether the overexpression of ATP-binding cassette (ABC) drug transporters such as ABCB1 and ABCG2, one of the most common mechanisms for developing multidrug resistance, may potentially reduce the efficacy of LY3023414 in human cancer cells. We demonstrated that the intracellular accumulation of LY3023414 in cancer cells was significantly reduced by the drug efflux function of ABCB1 and ABCG2. Consequently, the cytotoxicity and efficacy of LY3023414 for inhibiting the activation of the PI3K pathway and induction of G0/G1 cell-cycle arrest were substantially reduced in cancer cells overexpressing ABCB1 or ABCG2, which could be restored using tariquidar or Ko143, respectively. Furthermore, stimulatory effect of LY3023414 on the ATPase activity of ABCB1 and ABCG2, as well as in silico molecular docking analysis of LY3023414 binding to the substrate-binding pockets of these transporters provided additional insight into the manner in which LY3023414 interacts with both transporters. In conclusion, we report that LY3023414 is a substrate for ABCB1 and ABCG2 transporters implicating their role in the development of resistance to LY3023414, which can have substantial clinical implications and should be further investigated.
LY3023414（索拉非尼）是一种有前途的新型磷酸肌醇 3-激酶（PI3K）和哺乳动物雷帕霉素靶蛋白（mTOR）双重抑制剂。目前，多项临床试验正在评估 LY3023414 在各种类型癌症患者中的疗效。然而，人类癌细胞对 LY3023414 获得性耐药的潜在机制仍不清楚。在这项研究中，我们研究了是否过度表达 ABC 药物转运蛋白（如 ABCB1 和 ABCG2），这是产生多药耐药的最常见机制之一，可能会降低 LY3023414 在人类癌细胞中的疗效。我们证明，ABCB1 和 ABCG2 的药物外排功能显著降低了 LY3023414 在癌细胞中的积累。因此，在过度表达 ABCB1 或 ABCG2 的癌细胞中，LY3023414 抑制 PI3K 通路激活和诱导 G0/G1 细胞周期停滞的细胞毒性和疗效显著降低，分别使用 tariquidar 或 Ko143 可恢复这些作用。此外，LY3023414 对 ABCB1 和 ABCG2 的 ATP 酶活性的刺激作用以及 LY3023414 与这些转运体的底物结合口袋结合的计算机分子对接分析为 LY3023414 与两种转运体相互作用的方式提供了更多的见解。总之，我们报告 LY3023414 是 ABCB1 和 ABCG2 转运体的底物，这表明它们在 LY3023414 耐药性的发展中起作用，这可能具有重要的临床意义，应进一步研究。
