CBX5 loss drives EGFR inhibitor resistance and results in therapeutically actionable vulnerabilities in lung cancer.
CBX5 loss drives EGFR inhibitor resistance and results in therapeutically actionable vulnerabilities in lung cancer.
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DOI：
10.1073/pnas.2218118120
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发表时间：
2023-01-24
影响因子：
11.1
通讯作者：
Wajapeyee, Narendra
中科院分区：
文献类型：
--
作者：
Bugide, Suresh;Edwards, Yvonne J. K.;Gupta, Romi;Green, Michael R.;Wajapeyee, Narendra
15% 至 20% 的肺癌发生表皮生长因子受体 (EGFR) 突变。 EGFR 突变型肺癌患者通常使用称为 EGFR 抑制剂 (EGFRi) 的抗癌药物进行治疗，但治疗常常因获得性耐药而失败。在这里，我们证明表观遗传阻遏物 CBX5 的缺失通过一种涉及转录因子 E2F1 及其靶标抗凋亡蛋白 BIRC5（生存素）上调的机制赋予 EGFRi 耐药性。我们证明，通过恢复 CBX5 表达或抑制 BIRC5，对该 CBX5-E2F1-BIRC5 轴进行药理学抑制，代表了治疗 EGFRi 耐药性肺癌的治疗方法。我们的结果为因获得性耐药的出现而导致 EGFRi 治疗失败的 EGFR 突变型肺癌患者提供了潜在的治疗机会。尽管表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（EGFRi）被批准用于治疗 EGFR 突变型肺腺癌（LUAD），但获得性耐药的出现限制了其临床益处。已确定 LUAD 中 EGFRi 获得性耐药的几种机制；然而，约 30% 的 LUAD 中这种耐药性的分子基础仍然未知。染色质和 DNA 修饰剂及其调节剂在决定抗癌疗法的反应中发挥着重要作用。因此，为了确定 LUAD 中 EGFRi 耐药的非遗传机制，我们针对 363 个人类表观遗传调节基因进行了表观基因组范围的 shRNA 筛选。该筛选确定转录抑制因子染色体盒同源物 5 (CBX5) 的缺失是 EGFR 突变 LUAD 中 EGFRi 耐药的驱动因素。 CBX5 的缺失会导致细胞培养物和小鼠对多种 EGFRi 产生耐药性。我们发现 EGFR 突变 LUAD 细胞中 CBX5 的缺失导致转录因子 E2F1 表达增加，进而刺激抗凋亡基因 BIRC5（生存素）的表达。在 CBX5 敲低的 LUAD 细胞中，E2F1 介导的 BIRC5 上调减弱了 EGFRi 治疗后的细胞凋亡诱导。与这些结果一致，E2F1 或 BIRC5 的敲低可部分挽救细胞培养物和小鼠中 CBX5 敲低诱导的 EGFRi 抗性。与亲本细胞系相比，EGFRi 抗性 LUAD 细胞系表现出 CBX5 表达降低；然而，溴基和额外末端（BET）结构域抑制剂（BETi）可恢复这些细胞中的 CBX5 表达，并使它们对 EGFRi/BETi 联合疗法敏感。同样，使用 BIRC5 抑制剂治疗可抑制 EGFRi 耐药 LUAD 细胞的生长。总的来说，这些研究确定 CBX5 缺失是 EGFRi 耐药的驱动因素，并揭示了治疗 EGFRi 耐药 LUAD 的治疗机会。
Mutations in epidermal growth factor receptor (EGFR) occur in 15 to 20% of lung cancers. Patients with EGFR-mutant lung cancer are typically treated with anticancer drugs called EGFR inhibitors (EGFRi), but therapy often fails due to acquired drug resistance. Here, we show that loss of the epigenetic repressor CBX5 confers EGFRi resistance through a mechanism that involves upregulation of the transcription factor E2F1 and its target, the antiapoptotic protein BIRC5 (survivin). We demonstrate that pharmacological inhibition of this CBX5-E2F1-BIRC5 axis, through either restoration of CBX5 expression or inhibition of BIRC5, represents a therapeutic approach for treating EGFRi-resistant lung cancer. Our results provide potential treatment opportunities for EGFR-mutant lung cancer patients who have failed EGFRi therapy due to the emergence of acquired resistance. Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFRi) are approved for treating EGFR-mutant lung adenocarcinoma (LUAD), emergence of acquired resistance limits their clinical benefits. Several mechanisms for acquired resistance to EGFRi in LUAD have been identified; however, the molecular basis for this resistance remains unknown in ~30% of LUAD. Chromatin and DNA modifiers and their regulators play important roles in determining response to anticancer therapies. Therefore, to identify nongenetic mechanisms of EGFRi resistance in LUAD, we performed an epigenome-wide shRNA screen targeting 363 human epigenetic regulator genes. This screen identified loss of the transcriptional repressor chromobox homolog 5 (CBX5) as a driver of EGFRi resistance in EGFR-mutant LUAD. Loss of CBX5 confers resistance to multiple EGFRi in both cell culture and mice. We found that CBX5 loss in EGFR-mutant LUAD cells leads to increased expression of the transcription factor E2F1, which in turn stimulates expression of the antiapoptotic gene BIRC5 (survivin). This E2F1-mediated upregulation of BIRC5 in CBX5-knockdown LUAD cells attenuates apoptosis induction following EGFRi treatment. Consistent with these results, knockdown of E2F1 or BIRC5 partly rescues CBX5-knockdown-induced EGFRi resistance in cell culture and mice. EGFRi-resistant LUAD cell lines show reduced CBX5 expression compared to parental lines; however, bromo- and extra-terminal (BET)-domain inhibitors (BETi) restore CBX5 expression in these cells and sensitize them to EGFRi/BETi combination therapy. Similarly, treatment with a BIRC5 inhibitor suppresses growth of EGFRi-resistant LUAD cells. Collectively, these studies identify CBX5 loss as a driver of EGFRi resistance and reveal therapeutic opportunities for treating EGFRi-resistant LUAD.
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