The nontaxane microtubule inhibitor eribulin is an approved therapeutic for metastatic breast cancer and liposarcoma. Eribulin was previously tested in unselected patients with lung cancer and yielded a modest objective response rate of ∼5%–12%. Because lung cancers represent diverse histologies and driving oncogenic mutations, we postulated that eribulin may exhibit properties of a precision oncology agent with a previously undefined specificity for a molecularly distinct subset of lung cancers. Herein, we screened a panel of 44 non–small cell and small-cell lung cancer cell lines for in vitro growth sensitivity to eribulin. The results revealed a greater than 15,000-fold range in eribulin sensitivity (IC₅₀ = 0.005–89 nM) among the cell lines that was not correlated with their sensitivity to the taxane-based inhibitor paclitaxel. The quartile of cell lines exhibiting the lowest eribulin IC₅₀ values was not enriched for specific histologies, epithelial-mesenchymal differentiation, or specific oncogene drivers but was significantly enriched for nonsense/frameshift TP53 mutations and low-TP53 mRNA but not missense TP53 mutations. By comparison, the mutation status of cyclin-dependent kinase inhibitor 2A, STK11, and KEAP1 was not associated with eribulin sensitivity. Finally, the highest eribulin IC₅₀ quartile (>1 nM) exhibited significantly elevated mRNA expression of the drug pump, ATP binding cassette B1, defined resistance mechanism to eribulin, and paclitaxel. The findings support further investigations into basic mechanisms by which complete lack of TP53 function regulates anticancer activity of eribulin and the potential utility of TP53 null phenotypes distinct from TP53 missense mutations as a biomarker of response in patients with lung cancer.

中文翻译：

---

TP53 无效突变可识别对非紫杉烷微管抑制剂艾日布林最敏感的肺癌细胞系

非紫杉烷微管抑制剂艾日布林被批准用于治疗转移性乳腺癌和脂肪肉瘤。艾日布林之前曾在未经选择的肺癌患者中进行过测试，并产生了约 5% 至 12% 的适度客观反应率。因为肺癌代表不同的组织学和驱动致癌突变，我们假设艾日布林可能表现出精确肿瘤药物的特性，对肺癌的分子不同亚群具有以前未定义的特异性。在此，我们筛选了一组 44 种非小细胞和小细胞肺癌细胞系，以确定对艾日布林的体外生长敏感性。结果显示艾日布林的敏感性范围超过 15,000 倍 (IC ₅₀= 0.005–89 nM) 在与它们对基于紫杉烷的抑制剂紫杉醇的敏感性无关的细胞系中。表现出最低艾日布林 IC ₅₀值的四分位数细胞系没有富集特定组织学、上皮间充质分化或特定癌基因驱动因素，但显着富集无义/移码 TP53 突变和低 TP53 mRNA 但没有错义 TP53 突变。相比之下，细胞周期蛋白依赖性激酶抑制剂 2A、STK11 和 KEAP1 的突变状态与艾日布林敏感性无关。最后，最高艾日布林IC ₅₀四分位数 (>1 nM) 表现出药物泵、ATP 结合盒 B1、确定的艾日布林耐药机制和紫杉醇的 mRNA 表达显着升高。这些发现支持进一步研究完全缺乏 TP53 功能调节艾日布林抗癌活性的基本机制，以及与 TP53 错义突变不同的 TP53 无效表型作为肺癌患者反应的生物标志物的潜在效用。