Tumor Microenvironment and Cancer Immunology, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
Nat Commun. 2021 May 19;12(1):2940. doi: 10.1038/s41467-021-23271-0.
Resistance to endocrine treatment occurs in ~30% of ER breast cancer patients resulting in ~40,000 deaths/year in the USA. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance. However, clinical trials of pan-HER inhibitors in ER/HER2 patients have disappointed, likely due to a lack of predictive biomarkers. Here we demonstrate that loss of mismatch repair activates HER2 after endocrine treatment in ER/HER2 breast cancer cells by protecting HER2 from protein trafficking. Additionally, HER2 activation is indispensable for endocrine treatment resistance in MutL cells. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment. Patient data from multiple clinical datasets supports an association between MutL loss, HER2 upregulation, and sensitivity to HER inhibitors in ER/HER2 patients. These results provide strong rationale for MutL loss as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine intervention and HER inhibitors in endocrine treatment-resistant ER/HER2 breast cancer patients.
内分泌治疗耐药发生于约 30%的 ER 阳性乳腺癌患者，导致美国每年约有 4 万人因此死亡。临床前研究强烈提示生长因子受体 HER2 的激活与内分泌治疗耐药有关。然而，针对 ER/HER2 阳性患者的 pan-HER 抑制剂的临床试验令人失望，这可能是由于缺乏预测性生物标志物。在这里，我们证明错配修复缺失通过保护 HER2 免受蛋白转运，在内分泌治疗后激活 ER/HER2 乳腺癌细胞中的 HER2。此外，HER2 的激活对于 MutL 细胞中的内分泌治疗耐药是必不可少的。因此，抑制 HER2 可恢复对内分泌治疗的敏感性。来自多个临床数据集的患者数据支持 MutL 缺失、HER2 上调与 ER/HER2 患者对 HER 抑制剂的敏感性之间存在关联。这些结果为 MutL 缺失作为内分泌治疗耐药的 ER/HER2 乳腺癌患者联合内分泌干预和 HER 抑制剂治疗的敏感性的首创预测标志物提供了强有力的依据。
