UT Southwestern Simmons Comprehensive Cancer Center, Dallas, Texas.
Doctoral Program in Medical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
Cancer Res. 2023 Sep 15;83(18):3145-3158. doi: 10.1158/0008-5472.CAN-22-3617.
HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKI) 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. It is unknown whether these secondary HER2 mutations, other than the HER2T798I gatekeeper mutation, are causal to neratinib resistance. Herein, we show 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. 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. Together, these findings reveal the driver function of secondary HER2 mutations in resistance to HER2 inhibition and provide a potential treatment strategy to overcome acquired resistance to HER2 TKIs in HER2-mutant breast cancer.
HER2-mutant breast cancers acquire secondary HER2 mutations that drive resistance to HER2 tyrosine kinase inhibitors, which can be overcome by combined inhibition of HER2 and MEK.
HER2 突变驱动了一部分乳腺癌的生长，HER2 酪氨酸激酶抑制剂（TKI）如奈拉替尼可靶向 HER2 突变。然而，获得性耐药很常见，限制了临床反应的持久性。大多数在基于奈拉替尼的治疗中进展的 HER2 突变型乳腺癌会在 HER2 上获得继发性突变。尚不清楚除了 HER2T798I 看门突变之外的这些继发性 HER2 突变是否是导致奈拉替尼耐药的原因。在此，我们表明，继发性获得的 HER2T862A 和 HER2L755S 突变通过增强 HER2 激活和削弱奈拉替尼结合来促进对 HER2 TKI 的耐药性。虽然单独表达获得性 HER2 突变的细胞对奈拉替尼敏感，但表达获得性双突变会增强 HER2 信号并降低奈拉替尼敏感性。计算结构建模表明，继发性 HER2 突变稳定了 HER2 的激活状态并降低了奈拉替尼的结合亲和力。表达双 HER2 突变的细胞对大多数 HER2 TKI 表现出耐药性，但保留了对莫博赛替尼和波齐替尼的敏感性。双突变细胞表现出增强的 MEK/ERK 信号，该信号可通过联合抑制 HER2 和 MEK 来阻断。总之，这些发现揭示了继发性 HER2 突变在 HER2 抑制耐药中的驱动作用，并为克服 HER2 突变型乳腺癌中 HER2 TKI 的获得性耐药提供了一种潜在的治疗策略。
HER2 突变型乳腺癌获得了驱动 HER2 酪氨酸激酶抑制剂耐药的继发性 HER2 突变，可通过联合抑制 HER2 和 MEK 来克服。
