Yang Jinming, Luo Weifeng, Ward Patricia, Chen Sheau-Chiann, Zebala John, Maeda Dean, Yan Chi, Richmond Ann
Tennessee Valley Healthcare System (TVHS) Department of Veterans Affairs, Nashville, TN, United States.
Department of Pharmacology, Vanderbilt University, Nashville, TN, United States.
Front Oncol. 2025 Aug 19;15:1609735. doi: 10.3389/fonc.2025.1609735. eCollection 2025.
Inhibitors of cyclin-dependent kinase 4 and 6 (CDK4/6) are approved for the treatment of locally advanced or metastatic breast cancer, but not for melanoma.
In this study, we evaluated the effectiveness of the CDK4/6 inhibitor, palbociclib, the CDK2 inhibitor, PF-07104091, the dual CXCR1 and CXCR2 (CXCR1/2) antagonist, SX-682, and the combination of these inhibitors for effective treatment of melanoma in preclinical models.
Both palbociclib and SX-682 inhibited the growth of BRAF/NRAS B16-F10 and NRAS 1014 melanoma tumors and in both models, SX-682 created a more anti-tumor immune microenvironment. The combination effect was additive in the B16F10 model, but not in the 1014 model. In the B16F10 model, the addition of the CDK2 inhibitor, PF-07104091, overcame B16F10 acquired resistance to CDK4/6 inhibitors by suppressing the induction of cyclin D1 and E1 expression by palbociclib. In the less responsive 1014 cells, cyclin D1 was reduced, but cyclin E1 was induced in response to PF-07104091. However, in both models, combined treatment with palbociclib and PF-07104091 markedly suppressed cyclin A2, cyclin D1, cyclin E1 and pRB-S807/S811. Combining CDK4/6 and CDK2 inhibitors with the CXCR1/2 antagonist, SX-682, halted B16F10 tumor growth by blocking tumor cell proliferation and increasing the anti-tumor immune response in the tumor microenvironment.
The combination of all three inhibitors resulted in a tumor microenvironment characterized by increased IFNγ-producing CD4+ T cells, decreased CD4+FOXP3+ T regulatory cells (Tregs), and decreased IL-10-producing CD4+ T cells. This combination also decreased the percentage of CD8+ T cells that expressed PD-1 or TIM-3 and increased the ratio of MHCII+F4/80+ M1-like macrophages to CD206+F4/80+ M2-like macrophages. These data suggest that inhibiting CDK4/6 and CDK2, combined with antagonism of CXCR1/2, may be an effective treatment for BRAF wild-type melanoma tumors and NRAS mutant melanoma tumors that express Rb and are resistant to immune checkpoint inhibitors.
细胞周期蛋白依赖性激酶4和6（CDK4/6）抑制剂已被批准用于治疗局部晚期或转移性乳腺癌，但未被批准用于治疗黑色素瘤。
在本研究中，我们评估了CDK4/6抑制剂哌柏西利、CDK2抑制剂PF-07104091、双CXCR1和CXCR2（CXCR1/2）拮抗剂SX-682以及这些抑制剂的组合在临床前模型中有效治疗黑色素瘤的效果。
哌柏西利和SX-682均抑制了BRAF/NRAS B16-F10和NRAS 1014黑色素瘤肿瘤的生长，并且在这两种模型中，SX-682都创造了一个更具抗肿瘤免疫的微环境。在B16F10模型中联合用药效果呈相加性，但在1014模型中并非如此。在B16F10模型中，添加CDK2抑制剂PF-07104091可通过抑制哌柏西利诱导的细胞周期蛋白D1和E1表达来克服B16F10对CDK4/6抑制剂产生的耐药性。在反应较差的1014细胞中，细胞周期蛋白D1减少，但细胞周期蛋白E1在PF-07104091作用下被诱导。然而，在这两种模型中，哌柏西利和PF-07104091联合治疗均显著抑制了细胞周期蛋白A2、细胞周期蛋白D1、细胞周期蛋白E1和pRB-S807/S811。将CDK4/6和CDK2抑制剂与CXCR1/2拮抗剂SX-682联合使用，通过阻断肿瘤细胞增殖并增强肿瘤微环境中的抗肿瘤免疫反应，使B16F10肿瘤生长停止。
所有三种抑制剂联合使用导致肿瘤微环境的特征为产生IFNγ的CD4+T细胞增加、CD4+FOXP3+调节性T细胞（Tregs）减少以及产生IL-10的CD4+T细胞减少。这种联合用药还降低了表达PD-1或TIM-3的CD8+T细胞百分比，并增加了MHCII+F4/80+M1样巨噬细胞与CD206+F4/80+M2样巨噬细胞的比例。这些数据表明，抑制CDK4/6和CDK2，同时拮抗CXCR1/2，可能是治疗BRAF野生型黑色素瘤肿瘤以及表达Rb且对免疫检查点抑制剂耐药的NRAS突变黑色素瘤肿瘤的有效方法。
