Oncogene Biology Laboratory, Francis Crick Institute, London, UK.
Experimental Histopathology, Francis Crick Institute, London, UK.
Nat Commun. 2024 Sep 25;15(1):8146. doi: 10.1038/s41467-024-52324-3.
Mutant selective drugs targeting the inactive, GDP-bound form of KRAS have been approved for use in lung cancer, but resistance develops rapidly. Here we use an inhibitor, (RMC-4998) that targets RAS in its active, GTP-bound form, to treat KRAS mutant lung cancer in various immune competent mouse models. RAS pathway reactivation after RMC-4998 treatment could be delayed using combined treatment with a SHP2 inhibitor, which not only impacts tumour cell RAS signalling but also remodels the tumour microenvironment to be less immunosuppressive. In an immune inflamed model, RAS and SHP2 inhibitors in combination drive durable responses by suppressing tumour relapse and inducing development of immune memory. In an immune excluded model, combined RAS and SHP2 inhibition sensitises tumours to immune checkpoint blockade, leading to efficient tumour immune rejection. These preclinical results demonstrate the potential of the combination of RAS(ON) G12C-selective inhibitors with SHP2 inhibitors to sensitize tumours to immune checkpoint blockade.
针对 KRAS 无活性 GDP 结合形式的突变体选择性药物已被批准用于肺癌，但耐药性迅速发展。在这里，我们使用一种针对 RAS 活性 GTP 结合形式的抑制剂 (RMC-4998) 来治疗各种免疫功能正常的小鼠模型中的 KRAS 突变型肺癌。在用 RMC-4998 治疗后，通过联合使用 SHP2 抑制剂可以延迟 RAS 通路的再激活，这不仅会影响肿瘤细胞 RAS 信号，还会重塑肿瘤微环境，使其免疫抑制性降低。在免疫激活模型中，RAS 和 SHP2 抑制剂的联合使用通过抑制肿瘤复发和诱导免疫记忆的发展来驱动持久的反应。在免疫排斥模型中，联合使用 RAS 和 SHP2 抑制剂可使肿瘤对免疫检查点阻断敏感，从而有效地排斥肿瘤。这些临床前结果表明，RAS(ON) G12C 选择性抑制剂与 SHP2 抑制剂联合使用有可能使肿瘤对免疫检查点阻断敏感。
