The ERK pathway is critical in oncogenesis; aberrations in components of this pathway are common in approximately 30% of human cancers. ERK1/2 (ERK) regulates cell proliferation, differentiation, and survival and is the terminal node of the pathway. BRAF- and MEK-targeted therapies are effective in BRAF V600E/K metastatic melanoma and lung cancers; however, responses are short-lived due to emergence of resistance. Reactivation of ERK signaling is central to the mechanisms of acquired resistance. Therefore, ERK inhibition provides an opportunity to overcome resistance and leads to improved efficacy. In addition, KRAS-mutant cancers remain an unmet medical need in which ERK inhibitors may provide treatment options alone or in combination with other agents. Here, we report identification and activity of LY3214996, a potent, selective, ATP-competitive ERK inhibitor. LY3214996 treatment inhibited the pharmacodynamic biomarker, phospho-p90RSK1, in cells and tumors, and correlated with LY3214996 exposures and antitumor activities. In in vitro cell proliferation assays, sensitivity to LY3214996 correlated with ERK pathway aberrations. LY3214996 showed dose-dependent tumor growth inhibition and regression in xenograft models harboring ERK pathway alterations. Importantly, more than 50% target inhibition for up to 8 to 16 hours was sufficient for significant tumor growth inhibition as single agent in BRAF- and KRAS-mutant models. LY3214996 also exhibited synergistic combination benefit with a pan-RAF inhibitor in a KRAS-mutant colorectal cancer xenograft model. Furthermore, LY3214996 demonstrated antitumor activity in BRAF-mutant models with acquired resistance in vitro and in vivo. Based on these preclinical data, LY3214996 has advanced to an ongoing phase I clinical trial (NCT02857270).

中文翻译：

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ERK 抑制剂 LY3214996 靶向 ERK 通路驱动的癌症：实现精准医学的治疗方法

ERK 通路在肿瘤发生中至关重要；在大约 30% 的人类癌症中，该通路的成分异常是常见的。ERK1/2 (ERK) 调节细胞增殖、分化和存活，是该途径的终端节点。BRAF 和 MEK 靶向疗法对 BR​​AF V600E/K 转移性黑色素瘤和肺癌有效；然而，由于出现阻力，反应是短暂的。ERK 信号的重新激活是获得性耐药机制的核心。因此，ERK 抑制提供了克服耐药性并提高疗效的机会。此外，KRAS 突变癌症仍然是未满足的医疗需求，其中 ERK 抑制剂可以单独或与其他药物联合提供治疗选择。在这里，我们报告了 LY3214996 的鉴定和活性，这是一种有效的、选择性的、ATP 竞争性 ERK 抑制剂。LY3214996 治疗抑制了细胞和肿瘤中的药效生物标志物磷酸化 p90RSK1，并与 LY3214996 暴露和抗肿瘤活性相关。在体外细胞增殖试验中，对 LY3214996 的敏感性与 ERK 通路异常相关。LY3214996 在携带 ERK 通路改变的异种移植模型中显示出剂量依赖性的肿瘤生长抑制和消退。重要的是，在 BRAF 和 KRAS 突变模型中，作为单一药物，长达 8 至 16 小时的超过 50% 的靶标抑制足以显着抑制肿瘤生长。LY3214996 在 KRAS 突变的结直肠癌异种移植模型中还表现出与泛 RAF 抑制剂的协同组合益处。此外，LY3214996 在体外和体内获得性耐药的 BRAF 突变模型中显示出抗肿瘤活性。