Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan; Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Tokyo 108-8639, Japan.
EBioMedicine. 2015 Dec 12;3:54-66. doi: 10.1016/j.ebiom.2015.12.009. eCollection 2016 Jan.
The anaplastic lymphoma kinase (ALK) fusion oncogene is observed in 3%-5% of non-small cell lung cancer (NSCLC). Crizotinib and ceritinib, a next-generation ALK tyrosine kinase inhibitor (TKI) active against crizotinib-refractory patients, are clinically available for the treatment of ALK-rearranged NSCLC patients, and multiple next-generation ALK-TKIs are currently under clinical evaluation. These ALK-TKIs exhibit robust clinical activity in ALK-rearranged NSCLC patients; however, the emergence of ALK-TKI resistance restricts the therapeutic effect. To date, various secondary mutations or bypass pathway activation-mediated resistance have been identified, but large parts of the resistance mechanism are yet to be identified. Here, we report the discovery of p-glycoprotein (P-gp/ABCB1) overexpression as a ceritinib resistance mechanism in ALK-rearranged NSCLC patients. P-gp exported ceritinib and its overexpression conferred ceritinib and crizotinib resistance, but not to PF-06463922 or alectinib, which are next-generation ALK inhibitors. Knockdown of ABCB1 or P-gp inhibitors sensitizes the patient-derived cancer cells to ceritinib, in vitro and in vivo. P-gp overexpression was identified in three out of 11 cases with in ALK-rearranged crizotinib or ceritinib resistant NSCLC patients. Our study suggests that alectinib, PF-06463922, or P-gp inhibitor with ceritinib could overcome the ceritinib or crizotinib resistance mediated by P-gp overexpression.
间变性淋巴瘤激酶（ALK）融合癌基因存在于 3%-5%的非小细胞肺癌（NSCLC）中。克唑替尼和塞瑞替尼，一种针对克唑替尼耐药患者的下一代ALK 酪氨酸激酶抑制剂（TKI），已在临床上用于治疗ALK 重排的 NSCLC 患者，并且多种下一代 ALK-TKIs 目前正在临床评估中。这些 ALK-TKIs 在 ALK 重排的 NSCLC 患者中表现出强大的临床活性；然而，ALK-TKI 耐药的出现限制了治疗效果。迄今为止，已经确定了各种继发性突变或旁路途径激活介导的耐药性，但大部分耐药机制仍有待确定。在这里，我们报告了在 ALK 重排的 NSCLC 患者中发现 P-糖蛋白（P-gp/ABCB1）过表达作为塞瑞替尼耐药机制。P-gp 将塞瑞替尼输出，其过表达赋予了塞瑞替尼和克唑替尼耐药性，但对 PF-06463922 或艾乐替尼（下一代 ALK 抑制剂）没有作用。ABCB1 或 P-gp 抑制剂的敲低使源自患者的癌细胞对塞瑞替尼敏感，无论是在体外还是体内。在三例 ALK 重排的对克唑替尼或塞瑞替尼耐药的 NSCLC 患者中发现了 P-gp 过表达。我们的研究表明，艾乐替尼、PF-06463922 或 P-gp 抑制剂与塞瑞替尼联合使用可以克服由 P-gp 过表达介导的塞瑞替尼或克唑替尼耐药。
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