Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
Rain Therapeutics, Inc., Newark, California, USA.
Thorac Cancer. 2021 May;12(10):1511-1516. doi: 10.1111/1759-7714.13931. Epub 2021 Mar 12.
Approximately 10% of non-small cell lung cancers (NSCLCs) that harbor epidermal growth factor receptor (EGFR) gene mutations have in-frame insertions in exon 20 of the EGFR gene. These tumors do not usually respond to currently available EGFR-tyrosine kinase inhibitors (TKIs). Tarloxotinib is a novel hypoxia-activated prodrug that releases a potent, irreversible pan-ERBB TKI (tarloxotinib-E) under solid tumor hypoxia.
We examined the efficacy of tarloxotinib-E against several types of Ba/F3 cells with introduced EGFR exon 20 mutations (EGFR A763insFQEA, V769insASV, D770insSVD, H773insH and H773insNPH mutations). We assayed growth inhibition for tarloxotinib (prodrug), tarloxotinib-E (active form), poziotinib, afatinib, and osimertinib in Ba/F3 cells with each EGFR exon 20 mutation. We also explored acquired resistance mechanisms to tarloxotinib-E by establishing cells with resistance to tarloxotinib-E via chronic drug exposure after N-ethyl-N-nitrosourea mutagenesis treatment.
Among all tested Ba/F3 cell lines, IC was ≥72.1 times higher for tarloxotinib than for tarloxotinib-E, which implies a wide therapeutic window with this prodrug strategy. Tarloxotinib-E was efficacious against all tested Ba/F3 cells except for H773insH, which was less sensitive to all tested EGFR-TKIs. As acquired resistance mechanisms to tarloxotinib-E, we identified either T790M or C797S secondary mutations, depending on the original EGFR exon 20 mutation.
These findings indicate that tarloxotinib-E could be effective for NSCLC with EGFR exon 20 mutations. Our results also show that T790M or C797S mutations can confer acquired resistance to tarloxotinib-E; and suggest that resistance mechanisms are influenced by the baseline EGFR exon 20 mutations.
大约 10%的携带有表皮生长因子受体（EGFR）基因突变的非小细胞肺癌（NSCLC）患者，其 EGFR 基因外显子 20 中存在框内插入。这些肿瘤通常对目前可用的 EGFR 酪氨酸激酶抑制剂（TKI）没有反应。Tarloxotinib 是一种新型的低氧激活前药，在实体肿瘤低氧条件下释放一种有效的、不可逆的泛 ERBB TKI（tarloxotinib-E）。
我们研究了 tarloxotinib-E 对几种引入 EGFR 外显子 20 突变（EGFR A763insFQEA、V769insASV、D770insSVD、H773insH 和 H773insNPH 突变）的 Ba/F3 细胞的疗效。我们检测了 tarloxotinib（前药）、tarloxotinib-E（活性形式）、poziotinib、afatinib 和 osimertinib 在每种 EGFR 外显子 20 突变的 Ba/F3 细胞中的生长抑制作用。我们还通过用 N-乙基-N-亚硝基脲诱变处理后进行慢性药物暴露，建立对 tarloxotinib-E 耐药的细胞，以探索对 tarloxotinib-E 的获得性耐药机制。
在所有测试的 Ba/F3 细胞系中，tarloxotinib 的 IC 是 tarloxotinib-E 的≥72.1 倍，这表明这种前药策略具有很大的治疗窗口。Tarloxotinib-E 对所有测试的 Ba/F3 细胞均有效，除了 H773insH 对所有测试的 EGFR-TKI 均不敏感。作为对 tarloxotinib-E 的获得性耐药机制，我们根据原始 EGFR 外显子 20 突变，鉴定了 either T790M 或 C797S 二级突变。
这些发现表明 tarloxotinib-E 可能对 EGFR 外显子 20 突变的 NSCLC 有效。我们的结果还表明，T790M 或 C797S 突变可以赋予对 tarloxotinib-E 的获得性耐药性；并表明耐药机制受基线 EGFR 外显子 20 突变的影响。
