Wu Chung-Pu, Hung Cheng-Yu, Murakami Megumi, Wu Yu-Shan, Lin Chun-Ling, Huang Yang-Hui, Hung Tai-Ho, Yu Jau-Song, Ambudkar Suresh V
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
Cancers (Basel). 2022 May 9;14(9):2341. doi: 10.3390/cancers14092341.
Ensartinib (X-396) is a promising second-generation small-molecule inhibitor of anaplastic lymphoma kinase (ALK) that was developed for the treatment of ALK-positive non-small-cell lung cancer. Preclinical and clinical trial results for ensartinib showed superior efficacy and a favorable safety profile compared to the first-generation ALK inhibitors that have been approved by the U.S. Food and Drug Administration. Although the potential mechanisms of acquired resistance to ensartinib have not been reported, the inevitable emergence of resistance to ensartinib may limit its therapeutic application in cancer. In this work, we investigated the interaction of ensartinib with P-glycoprotein (P-gp) and ABCG2, two ATP-binding cassette (ABC) multidrug efflux transporters that are commonly associated with the development of multidrug resistance in cancer cells. Our results revealed that P-gp overexpression, but not expression of ABCG2, was associated with reduced cancer cell susceptibility to ensartinib. P-gp directly decreased the intracellular accumulation of ensartinib, and consequently reduced apoptosis and cytotoxicity induced by this drug. The cytotoxicity of ensartinib could be significantly reversed by treatment with the P-gp inhibitor tariquidar. In conclusion, we report that ensartinib is a substrate of P-gp, and provide evidence that this transporter plays a role in the development of ensartinib resistance. Further investigation is needed.
恩扎替尼（X-396）是一种有前景的第二代间变性淋巴瘤激酶（ALK）小分子抑制剂，用于治疗ALK阳性非小细胞肺癌。与美国食品药品监督管理局批准的第一代ALK抑制剂相比，恩扎替尼的临床前和临床试验结果显示出更高的疗效和良好的安全性。尽管尚未报道对恩扎替尼获得性耐药的潜在机制，但对恩扎替尼不可避免的耐药出现可能会限制其在癌症治疗中的应用。在这项研究中，我们研究了恩扎替尼与P-糖蛋白（P-gp）和ABCG2的相互作用，这两种ATP结合盒（ABC）多药外排转运蛋白通常与癌细胞多药耐药的发生有关。我们的结果显示，P-gp过表达而非ABCG2表达与癌细胞对恩扎替尼的敏感性降低有关。P-gp直接降低了恩扎替尼的细胞内蓄积，从而减少了该药物诱导的细胞凋亡和细胞毒性。用P-gp抑制剂他林洛尔治疗可显著逆转恩扎替尼的细胞毒性。总之，我们报道恩扎替尼是P-gp的底物，并提供证据表明该转运蛋白在恩扎替尼耐药的发生中起作用。还需要进一步研究。
