Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.).
Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.)
J Pharmacol Exp Ther. 2023 May;385(2):106-116. doi: 10.1124/jpet.122.001431. Epub 2023 Feb 27.
Individuals with neurofibromatosis type 1 develop rat sarcoma virus (RAS)-mitogen-activated protein kinase-mitogen-activated and extracellular signal-regulated kinase (RAS-MAPK-MEK)-driven nerve tumors called neurofibromas. Although MEK inhibitors transiently reduce volumes of most plexiform neurofibromas in mouse models and in neurofibromatosis type 1 (NF1) patients, therapies that increase the efficacy of MEK inhibitors are needed. BI-3406 is a small molecule that prevents Son of Sevenless (SOS)1 interaction with Kirsten rat sarcoma viral oncoprotein (KRAS)-GDP, interfering with the RAS-MAPK cascade upstream of MEK. Single agent SOS1 inhibition had no significant effect in the DhhCre;Nf1 mouse model of plexiform neurofibroma, but pharmacokinetics (PK)-driven combination of selumetinib with BI-3406 significantly improved tumor parameters. Tumor volumes and neurofibroma cell proliferation, reduced by MEK inhibition, were further reduced by the combination. Neurofibromas are rich in ionized calcium binding adaptor molecule 1 (Iba1)+ macrophages; combination treatment resulted in small and round macrophages, with altered cytokine expression indicative of altered activation. The significant effects of MEK inhibitor plus SOS1 inhibition in this preclinical study suggest potential clinical benefit of dual targeting of the RAS-MAPK pathway in neurofibromas. SIGNIFICANCE STATEMENT: Interfering with the RAS-mitogen-activated protein kinase (RAS-MAPK) cascade upstream of mitogen activated protein kinase kinase (MEK), together with MEK inhibition, augment effects of MEK inhibition on neurofibroma volume and tumor macrophages in a preclinical model system. This study emphasizes the critical role of the RAS-MAPK pathway in controlling tumor cell proliferation and the tumor microenvironment in benign neurofibromas.
患有神经纤维瘤病 1 型的个体可发展出鼠肉瘤病毒（RAS）-有丝分裂原激活的蛋白激酶-有丝分裂原和细胞外信号调节激酶（RAS-MAPK-MEK）驱动的神经肿瘤，称为神经纤维瘤。尽管 MEK 抑制剂可短暂减少鼠模型和神经纤维瘤病 1 型（NF1）患者中大多数丛状神经纤维瘤的体积，但仍需要提高 MEK 抑制剂疗效的治疗方法。BI-3406 是一种小分子，可阻止 Son of Sevenless（SOS）1 与 Kirsten 大鼠肉瘤病毒致癌蛋白（KRAS）-GDP 的相互作用，从而干扰 MEK 上游的 RAS-MAPK 级联反应。单独的 SOS1 抑制在 DhhCre；Nf1 鼠丛状神经纤维瘤模型中没有明显作用，但药代动力学（PK）驱动的 selumetinib 与 BI-3406 的联合应用显著改善了肿瘤参数。MEK 抑制减少的肿瘤体积和神经纤维瘤细胞增殖，通过联合治疗进一步减少。神经纤维瘤富含离子钙结合衔接分子 1（Iba1）+巨噬细胞；联合治疗导致巨噬细胞变小变圆，细胞因子表达改变提示激活改变。这项临床前研究中 MEK 抑制剂加 SOS1 抑制的显著效果表明，RAS-MAPK 通路的双重靶向在神经纤维瘤中具有潜在的临床获益。意义：干扰 MEK 激酶（MEK）上游的 RAS-有丝分裂原激活的蛋白激酶（RAS-MAPK）级联反应，与 MEK 抑制一起，可增强 MEK 抑制对神经纤维瘤体积和肿瘤巨噬细胞的影响在临床前模型系统中。这项研究强调了 RAS-MAPK 通路在控制肿瘤细胞增殖和良性神经纤维瘤肿瘤微环境中的关键作用。
