HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKIs) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2. Apart from the HER2T798I gatekeeper mutation, whether these secondary HER2 mutations are causal to neratinib resistance is not known. We show herein that secondary acquired HER2T862A and HER2L755S mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired HER2 mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity in 2D and 3D assays. Computational structural modeling suggested that secondary HER2 mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib. Double-mutant cells showed enhanced MEK/ERK signaling which was blocked by combined inhibition of HER2 and MEK, providing a potential treatment strategy to overcome resistance to HER2 TKIs in HER2-mutant breast cancer.

中文翻译：

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获得性继发性 HER2 突变增强 HER2/MAPK 信号传导并促进 HER2 突变乳腺癌对 HER2 激酶抑制的抗性

HER2 突变驱动一部分乳腺癌的生长，并以 HER2 酪氨酸激酶抑制剂 (TKI) 为目标，例如来那替尼。然而，获得性耐药很常见，并限制了临床反应的持久性。大多数在以来那替尼为基础的治疗中进展的 HER2 突变乳腺癌在 HER2 中获得了继发性突变。除了 HER2T798I 看门人突变外，这些继发性 HER2 突变是否是来那替尼耐药的原因尚不清楚。我们在此显示，继发性获得性 HER2T862A 和 HER2L755S 突变通过增强 HER2 活化和受损的来那替尼结合来促进对 HER2 TKI 的抗性。虽然单独表达每个获得性 HER2 突变的细胞对来那替尼敏感，但获得性双突变的表达增强了 HER2 信号传导并降低了 2D 和 3D 测定中来那替尼的敏感性。计算结构模型表明，继发性 HER2 突变稳定 HER2 活性状态并降低来那替尼结合亲和力。表达双 HER2 突变的细胞对大多数 HER2 TKI 表现出抗性，但对 mobocertinib 和 poziotinib 保持敏感性。双突变细胞表现出增强的 MEK/ERK 信号传导，这被 HER2 和 MEK 的联合抑制所阻断，为克服 HER2 突变乳腺癌中对 HER2 TKI 的耐药性提供了一种潜在的治疗策略。