Department of Breast Surgery, Shanghai Cancer Center and Cancer Institute, Shanghai Medical College, Fudan University, Shanghai, China.
Key Laboratory of Breast Cancer in Shanghai, Shanghai, China.
JCI Insight. 2023 Nov 22;8(22):e172366. doi: 10.1172/jci.insight.172366.
To provide complementary information and reveal the molecular characteristics and therapeutic insights of HER2-low breast cancer, we performed this multiomics study of hormone receptor-negative (HR-) and HER2-low breast cancer, also known as HER2-low triple-negative breast cancer (TNBC), and identified 3 subgroups: basal-like, receptor tyrosine kinase-relevant (TKR), and mesenchymal stem-like. These 3 subgroups had distinct features and potential therapeutic targets and were validated in external data sets. Interestingly, the TKR subgroup (which exists in both HR+ and HR- breast cancer) had activated HER2 and downstream MAPK signaling. In vitro and in vivo patient-derived xenograft experiments revealed that pretreatment of the TKR subgroup with a tyrosine kinase inhibitor (lapatinib or tucatinib) could inhibit HER2 signaling and induce accumulated expression of nonfunctional HER2, resulting in increased sensitivity to the sequential HER2-targeting, Ab-drug conjugate DS-8201. Our findings identify clinically relevant subgroups and provide potential therapeutic strategies for HER2-low TNBC subtypes.
为了提供补充信息，并揭示 HER2 低表达乳腺癌的分子特征和治疗见解，我们对激素受体阴性（HR-）和 HER2 低表达乳腺癌（也称为 HER2 低表达三阴性乳腺癌 [TNBC]）进行了这项多组学研究，并鉴定出 3 个亚组：基底样、受体酪氨酸激酶相关（TKR）和间充质干细胞样。这 3 个亚组具有不同的特征和潜在的治疗靶点，并在外部数据集得到验证。有趣的是，TKR 亚组（存在于 HR+和 HR-乳腺癌中）具有激活的 HER2 和下游 MAPK 信号。体外和体内患者来源的异种移植实验表明，用酪氨酸激酶抑制剂（拉帕替尼或图卡替尼）预处理 TKR 亚组可抑制 HER2 信号，并诱导非功能性 HER2 的积累表达，从而增加对顺序 HER2 靶向、Ab-药物偶联物 DS-8201 的敏感性。我们的研究结果确定了具有临床意义的亚组，并为 HER2 低表达 TNBC 亚型提供了潜在的治疗策略。
