吉列替尼克服 ALK 重排癌症中的洛拉替尼耐药性。

Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer.

机构信息

Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.

Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Kanagawa, Japan.

出版信息

Nat Commun. 2021 Feb 24;12(1):1261. doi: 10.1038/s41467-021-21396-w.

ALK gene rearrangement was observed in 3%-5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI-resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

ALK 基因重排可见于 3%-5%的非小细胞肺癌患者，随后依次使用了多种 ALK 酪氨酸激酶抑制剂（TKI）。从患者中已经鉴定出多种 ALK-TKI 耐药突变，一些复合突变，如 I1171N+F1174I 或 I1171N+L1198H，对所有已批准的 ALK-TKI 均耐药。在这项研究中，我们发现 gilteritinib 在体外和体内对 ALK-TKI 耐药的单突变体和 I1171N 复合突变体具有抑制作用。令人惊讶的是，在阿来替尼或劳拉替尼治疗后，EML4-ALK I1171N+F1174I 复合突变体表达的肿瘤并未完全缩小，而是在短时间内重新生长。然而，在体内模型中切换至 gilteritinib 后，复发的肿瘤明显缩小。此外，gilteritinib 对包括 entrectinib 耐药的 NTRK1 G667C 突变和 ROS1 融合阳性癌症在内的 NTRK 重排癌症有效。