Noda Takumi, Tanaka Saori, Maruta Yuto, Haruna Moe, Mizuguchi Serina, Fujimoto Ayumi, Urashima Kazuya, Kohda Yuka, Kato Ryuji
Department of Pharmacotherapeutics and Toxicology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Osaka 569-1094, Japan.
Department of Pharmacotherapeutics and Toxicology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Osaka 569-1094, Japan.
Toxicol Appl Pharmacol. 2025 May;498:117310. doi: 10.1016/j.taap.2025.117310. Epub 2025 Mar 21.
Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including brigatinib, are widely used to treat ALK-positive non-small cell lung cancer. However, severe adverse effects associated with brigatinib, such as interstitial pneumonia and liver dysfunction, may involve immune system activation. The precise mechanisms underlying these immune-related adverse effects remain unclear. In this study, we evaluated the direct activation of inflammasomes by brigatinib and other ALK TKI (crizotinib, alectinib, ceritinib) in differentiated THP-1 cells. Additionally, we analyzed the inflammasome-activating potential of supernatants from functional liver cell (FLC)-4 cells treated with these drugs. Our results demonstrate that brigatinib directly activates inflammasomes in THP-1 cells, inducing the production of interleukin-1β and the activation of caspase-1. In contrast, no inflammasome activation was observed with the other ALK TKIs. Furthermore, supernatants from FLC-4 cells, characterized by high drug-metabolizing activity, were shown to activate inflammasomes in differentiated THP-1 cells following treatment with brigatinib. Brigatinib treatment significantly increased the levels of damage-associated molecular patterns (DAMPs), including heat shock protein 90 and S100A6, in the supernatants of FLC-4 cells. These findings suggest that brigatinib induces the release of DAMPs from hepatocytes, which subsequently activate inflammasomes. This mechanism may be essential for brigatinib-induced immune system activation and the development of immune-related adverse events.
间变性淋巴瘤激酶（ALK）酪氨酸激酶抑制剂（TKI），包括布加替尼，被广泛用于治疗ALK阳性非小细胞肺癌。然而，与布加替尼相关的严重不良反应，如间质性肺炎和肝功能障碍，可能涉及免疫系统激活。这些免疫相关不良反应的具体机制仍不清楚。在本研究中，我们评估了布加替尼和其他ALK TKI（克唑替尼、阿来替尼、色瑞替尼）在分化的THP-1细胞中对炎性小体的直接激活作用。此外，我们分析了用这些药物处理的功能性肝细胞（FLC）-4细胞上清液的炎性小体激活潜力。我们的结果表明，布加替尼直接激活THP-1细胞中的炎性小体，诱导白细胞介素-1β的产生和半胱天冬酶-1的激活。相比之下，其他ALK TKI未观察到炎性小体激活。此外，具有高药物代谢活性的FLC-4细胞上清液在布加替尼处理后被证明可激活分化的THP-1细胞中的炎性小体。布加替尼处理显著增加了FLC-4细胞上清液中损伤相关分子模式（DAMPs）的水平，包括热休克蛋白90和S100A6。这些发现表明，布加替尼诱导肝细胞释放DAMPs，随后激活炎性小体。这种机制可能对布加替尼诱导的免疫系统激活和免疫相关不良事件的发生至关重要。
