Rios-Doria Jonathan, Favata Margaret, Lasky Kerri, Feldman Patricia, Lo Yvonne, Yang Gengjie, Stevens Christina, Wen Xiaoming, Sehra Sarita, Katiyar Kamna, Liu Ke, Wynn Richard, Harris Jennifer J, Ye Min, Spitz Susan, Wang Xiaozhao, He Chunhong, Li Yun-Long, Yao Wenqing, Covington Maryanne, Scherle Peggy, Koblish Holly
Incyte Research Institute, Wilmington, DE, United States.
Front Oncol. 2020 Dec 7;10:598477. doi: 10.3389/fonc.2020.598477. eCollection 2020.
TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases, which play important roles in tumor growth, survival, cell adhesion, as well as innate immunity, phagocytosis, and immune-suppressive activity. Therefore, targeting both AXL and MERTK kinases may directly impact tumor growth and relieve immunosuppression. We describe here the discovery of INCB081776, a potent and selective dual inhibitor of AXL and MERTK that is currently in phase 1 clinical trials. In cellular assays, INCB081776 effectively blocked autophosphorylation of AXL or MERTK with low nanomolar half maximal inhibitory concentration values in tumor cells and Ba/F3 cells transfected with constitutively active AXL or MERTK. INCB081776 inhibited activation of MERTK in primary human macrophages and partially reversed M2 macrophage-mediated suppression of T-cell proliferation, which was associated with increased interferon-γ production. , the antitumor activity of INCB081776 was enhanced in combination with checkpoint blockade in syngeneic models, and resulted in increased proliferation of intratumoral CD4 and CD8 T cells. Finally, antitumor activity of INCB081776 was observed in a subset of sarcoma patient-derived xenograft models, which was linked with inhibition of phospho-AKT. These data support the potential therapeutic utility of INCB081776 as an immunotherapeutic agent capable of both enhancing tumor immune surveillance and blocking tumor cell survival mechanisms.
TYRO3、AXL和MERTK构成受体酪氨酸激酶的TAM家族，它们在肿瘤生长、存活、细胞黏附以及先天免疫、吞噬作用和免疫抑制活性中发挥重要作用。因此，靶向AXL和MERTK激酶可能直接影响肿瘤生长并缓解免疫抑制。我们在此描述了INCB081776的发现，它是一种强效且选择性的AXL和MERTK双重抑制剂，目前正处于1期临床试验阶段。在细胞试验中，INCB081776在肿瘤细胞和转染了组成型活性AXL或MERTK的Ba/F3细胞中，以低纳摩尔的半数最大抑制浓度值有效阻断AXL或MERTK的自磷酸化。INCB081776抑制原代人巨噬细胞中MERTK的激活，并部分逆转M2巨噬细胞介导的T细胞增殖抑制，这与干扰素-γ产生增加有关。此外，在同基因模型中，INCB081776与检查点阻断联合使用时抗肿瘤活性增强，并导致肿瘤内CD4和CD8 T细胞增殖增加。最后，在一部分肉瘤患者来源的异种移植模型中观察到了INCB081776的抗肿瘤活性，这与磷酸化AKT的抑制有关。这些数据支持了INCB081776作为一种既能增强肿瘤免疫监视又能阻断肿瘤细胞存活机制的免疫治疗药物的潜在治疗效用。
