While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy. Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAFwt and BRAFmut melanoma and analyzed in reference to patient data. RGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8+ cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40+SOX10+ melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB. Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone. NCT01205815 (Sept 17, 2010).

中文翻译：

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具有 RAS/RAF/PI3K 通路抑制作用的肿瘤细胞对 CD40 表达的新诱导增强了对检查点阻断的反应

虽然免疫检查点阻断 (ICB) 是目前转移性黑色素瘤的一线治疗方法，但它对约 52% 的患者有效，并且具有危险的副作用。这里的目的是确定黑色素瘤中 RAS/RAF/PI3K 通路抑制以使肿瘤对 ICB 治疗敏感的可行性和机制。Rigosertib (RGS) 是一种非 ATP 竞争性小分子 RAS 模拟物。使用 BRAFwt 和 BRAFmut 黑色素瘤的免疫活性小鼠模型研究了 RGS 单一疗法或与 ICB 的联合疗法，并参考患者数据进行了分析。RGS 治疗 (300 mg/kg) 在小鼠中具有良好的耐受性，单药治疗可抑制约 50% 的肿瘤生长，与 αPD1 + αCTLA4 联合使用可抑制约 70% 的肿瘤生长。RGS 诱导的肿瘤生长抑制取决于黑色素瘤细胞中 CD40 的上调，然后是免疫原性细胞死亡，导致肿瘤微环境中的树突状细胞和活化的 T 细胞富集。RGS 启动的肿瘤抑制被黑色素瘤细胞中 CD40 表达的敲低或 CD8+ 细胞毒性 T 细胞的消耗部分逆转。使用 dabrafenib 和曲美替尼或 RGS 治疗，黑色素瘤患者和患者来源的异种移植物肿瘤中的 CD40+SOX10+ 黑色素瘤细胞增加。在黑色素瘤患者的 TCGA 数据集中，高 CD40 表达水平与有益的 T 细胞反应和更好的存活率相关。黑素瘤细胞的 CD40 表达与对 RAF/MEK 抑制和 ICB 的治疗反应有关。我们的数据支持 RGS + αPD1 + αCTLA4 在 RAS/RAF/PI3K 通路激活的黑色素瘤中的治疗用途，并指出需要对单独对 ICB 无反应的黑色素瘤患者进行 RGS + ICB 临床试验。NCT01205815（2010 年 9 月 17 日）。