Transmembrane and Juxtamembrane Domain Mutations Activate HER2

HER2 is frequently deregulated in cancer, leading to oncogenic signaling that drives tumorigenesis. Several HER2-targeted antibodies and small molecules have been approved for the treatment of HER2-driven tumors. HER2 dysregulation occurs most commonly by HER2 overexpression, but amplifications and mutations have also been identified. Oncogenic mutations in the HER2 extracellular domain and kinase domain have been characterized, but the effects of mutations in the transmembrane domain (TMD) and juxtamembrane domain (JMD), which occur at low frequency, have not been determined. Pahuja, Nguyen, Jaiswal, and colleagues sought to determine if mutations in the HER2 TMD and JMD promote tumorigenesis, and if these mutations might sensitize tumors to HER2-targeted therapies. Analysis of targeted exome-sequencing data from 111,176 tumors from 400 tumor types uncovered HER2 mutations in 3,851 tumors (3.5%). Approximately 2.8% of these mutations occurred in the TMD, and 7.7% occurred in the JMD. A saturation mutagenesis screen revealed several patient-derived HER2 TMD and JMD mutations that resulted in HER2 activation. Structural modeling indicated that these mutations activate HER2 by stabilizing the heterodimeric configuration required for active signaling or stabilizing the active dimer interface required for allosteric activation of HER2 receptor kinase activity. In vitro and in vivo, cells expressing HER2 TMD or JMD mutants were sensitive to anti-HER2 antibodies and kinase inhibitors. Further, a patient with lung cancer with the HER2 G660D mutation in the TMD responded to treatment with the HER2 inhibitor afatinib. The response was durable, lasting for more than 15 months, and the treatment was well tolerated. Collectively, these findings demonstrate that HER2 TMD and JMD mutations are oncogenic and suggest that patients harboring these mutations may benefit from HER2-targeted therapies.

Pahuja KB, Nguyen TT, Jaiswal BS, Prabhash K, Thaker TM, Senger K, et al. Actionable activating oncogenic ERBB2/HER2 transmembrane and juxtamembrane domain mutations. Cancer Cell 2018;34:792–806.E5.

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