陆军军医大学、重庆大学何勇研究组最新研究表明，布格替尼是一种新发现的AXL抑制剂，可抑制EGFR（表皮生长因子受体酪氨酸激酶抑制剂）突变的非小细胞肺癌中AXL介导的对奥希替尼的获得性耐药。这一研究成果于2024年3月4日发表在国际顶尖学术期刊《中国药理学报》上。

在这项研究中，研究团队评估了布格替尼(第二代间变性淋巴瘤激酶(ALK)-TKI)作为一种新型AXL抑制剂，在克服由AXL激活引起的对奥希替尼获得性耐药的疗效。研究人员建立了AXL过表达的非小细胞肺癌的细胞系，并对包含510种抗肿瘤药物的小分子化学文库进行了高通量筛选。该课题组人员发现布格替尼能有效抑制AXL的表达，并且布格替尼(0.5 μM)能显著增强奥希替尼(1 μM)对AXL介导的耐奥希替尼非小细胞肺癌细胞的抗肿瘤作用。课题组研究人员证明了布加替尼在非小细胞肺癌细胞系中，具有结合AXL激酶蛋白并进一步抑制其下游途径的潜在能力。

此外，该团队发现布加替尼可能通过增加HCC827OR细胞和PC-9OR细胞中，AXL的K48连锁泛素化和促进AXL降解来降低AXL的表达。在AXL高表达的耐奥西替尼的PC-9OR和HCC827OR细胞来源的移植小鼠模型中，奥西替尼(10mg·kg^-1·d^-1)单独给药3周无影响，布格替尼(25mg·kg^-1·d-¹)单独给药3周对肿瘤生长有轻微抑制；而奥希替尼和布格替尼联合使用可显著缩小肿瘤。

研究小组得出结论，布格替尼可能是一种有前景的临床策略，可提高奥西替尼对AXL介导的奥西替尼耐药非小细胞肺癌患者的疗效。

研究人员表示，除了经典的耐药机制外，受体酪氨酸蛋白激酶AXL是EGFR突变的非小细胞肺癌(NSCLC)对EGFR-TKI奥西替尼耐药的主要机制。开发有效的AXL抑制剂对实现奥希替尼的增敏具有重要意义。

附：原文原文

Title: Brigatinib, a newly discovered AXL inhibitor, suppresses AXL-mediated acquired resistance to osimertinib in EGFR-mutated non-small cell lung cancer

Author: Han, Rui, Lu, Cong-hua, Hu, Chen, Dou, Yuan-yao, Kang, Jun, Lin, Cai-yu, Wu, Di, Jiang, Wei-ling, Yin, Guo-qing, He, Yong

Issue&Volume: 2024-03-04

Abstract: In addition to the classical resistance mechanisms, receptor tyrosine-protein kinase AXL is a main mechanism of resistance to third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) osimertinib in EGFR-mutated non-small cell lung cancer (NSCLC). Developing an effective AXL inhibitor is important to sensitize osimertinib in clinical application. In this study we assessed the efficacy of brigatinib, a second-generation of anaplastic lymphoma kinase (ALK)-TKI, as a novel AXL inhibitor, in overcoming acquired resistance to osimertinib induced by AXL activation. We established an AXL-overexpression NSCLC cell line and conducted high-throughput screening of a small molecule chemical library containing 510 anti-tumor drugs. We found that brigatinib potently inhibited AXL expression, and that brigatinib (0.5μM) significantly enhanced the anti-tumor efficacy of osimertinib (1μM) in AXL-mediated osimertinib-resistant NSCLC cell lines in vitro. We demonstrated that brigatinib had a potential ability to bind AXL kinase protein and further inhibit its downstream pathways in NSCLC cell lines. Furthermore, we revealed that brigatinib might decrease AXL expression through increasing K48-linked ubiquitination of AXL and promoting AXL degradation in HCC827OR cells and PC-9OR cells. In AXL-high expression osimertinib-resistant PC-9OR and HCC827OR cells derived xenograft mouse models, administration of osimertinib (10mg·kg1·d1) alone for 3 weeks had no effect, and administration of brigatinib (25mg·kg1·d1) alone caused a minor inhibition on the tumor growth; whereas combination of osimertinib and brigatinib caused marked tumor shrinkages. We concluded that brigatinib may be a promising clinical strategy for enhancing osimertinib efficacy in AXL-mediated osimertinib-resistant NSCLC patients.

DOI: 10.1038/s41401-024-01237-4

Source: https://www.nature.com/articles/s41401-024-01237-4