Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd, Tsukuba, Japan.
Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
Cancer Sci. 2023 Feb;114(2):654-664. doi: 10.1111/cas.15617. Epub 2022 Nov 13.
Genetic alterations in human epidermal growth factor receptor type 2 (HER2)/epidermal growth factor receptor (EGFR) are commonly associated with breast and lung cancers and glioblastomas. Cancers with avian erythroblastosis oncogene B (ERBB) deregulation are highly metastatic and can cause primary brain tumors. Currently, no pan-ERBB inhibitor with remarkable brain penetration is available. Here, TAS2940, a novel irreversible pan-ERBB inhibitor with improved brain penetrability, was evaluated for its efficacy against several ERBB aberrant cancer models. The selectivity of TAS2940 was evaluated by enzymatic kinase assays. The inhibitory effects of TAS2940 against ERBB genetic alterations were examined using MCF10A cells expressing various HER2 or EGFR mutations and other generic cell lines harboring deregulated ERBB expression. In vivo efficacy of TAS2940 was examined following oral treatment in subcutaneous or intracranial xenograft cancer models. TAS2940 was highly potent against cells harboring HER2/EGFR alterations. TAS2940 could selectively inhibit phosphorylation of targets and the growth of cancer cells with ERBB aberrations in vitro. TAS2940 also inhibited tumor growth in xenograft mouse models with ERBB aberrations: HER2 amplification, HER2/EGFR exon 20 insertions, and EGFR vIII mutation. TAS2940 was effective in the intracranial xenograft models of HER2/EGFR cancers and improved the survival of these mice. TAS2940 has promising therapeutic effects in preclinical study against cancers harboring HER2/EGFR mutations, especially metastatic and primary brain tumors. Our results highlight potential novel strategies against lung cancers with brain metastases harboring HER2/EGFR exon 20 insertions and glioblastomas with EGFR aberrations.
人类表皮生长因子受体 2（HER2）/表皮生长因子受体（EGFR）的遗传改变通常与乳腺癌、肺癌和胶质母细胞瘤有关。具有禽类红细胞生成素癌基因 B（ERBB）失调的癌症具有高度转移性，并可能导致原发性脑肿瘤。目前，尚无具有显著脑穿透性的泛 ERBB 抑制剂。在这里，TAS2940 是一种新型的不可逆的泛 ERBB 抑制剂，具有改善的脑穿透性，用于评估其对几种 ERBB 异常癌症模型的疗效。通过酶激酶测定评估 TAS2940 的选择性。使用表达各种 HER2 或 EGFR 突变的 MCF10A 细胞和其他具有失调 ERBB 表达的通用细胞系，检查 TAS2940 对 ERBB 遗传改变的抑制作用。在皮下或颅内异种移植癌症模型中进行口服治疗后，检查 TAS2940 的体内疗效。TAS2940 对携带 HER2/EGFR 改变的细胞具有高度效力。TAS2940 可以选择性地抑制靶标磷酸化和体外具有 ERBB 异常的癌细胞生长。TAS2940 还抑制具有 ERBB 异常的异种移植小鼠模型中的肿瘤生长：HER2 扩增、HER2/EGFR 外显子 20 插入和 EGFR vIII 突变。TAS2940 在 HER2/EGFR 癌症的颅内异种移植模型中有效，并改善了这些小鼠的存活率。TAS2940 在针对携带 HER2/EGFR 突变的癌症的临床前研究中具有有前途的治疗效果，特别是转移性和原发性脑肿瘤。我们的结果突出了针对具有 HER2/EGFR 外显子 20 插入的肺癌和具有 EGFR 异常的胶质母细胞瘤的潜在新策略。
