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- W4386779891 abstract "<div>Abstract<p><i>HER2</i> 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 <i>HER2</i>-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in <i>HER2</i>. It is unknown whether these secondary <i>HER2</i> mutations, other than the <i>HER2<sup>T798I</sup></i> gatekeeper mutation, are causal to neratinib resistance. Herein, we show that secondary acquired <i>HER2<sup>T862A</sup></i> and <i>HER2<sup>L755S</sup></i> mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired <i>HER2</i> mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity. Computational structural modeling suggested that secondary <i>HER2</i> mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double <i>HER2</i> 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 <i>HER2</i> mutations in resistance to HER2 inhibition and provide a potential treatment strategy to overcome acquired resistance to HER2 TKIs in <i>HER2</i>-mutant breast cancer.</p>Significance:<p><i>HER2</i>-mutant breast cancers acquire secondary <i>HER2</i> mutations that drive resistance to HER2 tyrosine kinase inhibitors, which can be overcome by combined inhibition of HER2 and MEK.</p></div>" @default.
- W4386779891 created "2023-09-16" @default.
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- W4386779891 date "2023-09-15" @default.
- W4386779891 modified "2023-09-26" @default.
- W4386779891 title "Data from Acquired Secondary <i>HER2</i> Mutations Enhance HER2/MAPK Signaling and Promote Resistance to HER2 Kinase Inhibition in Breast Cancer" @default.
- W4386779891 doi "https://doi.org/10.1158/0008-5472.c.6836993" @default.
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