We report a gatekeeper mutation in a patient with -mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2 reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2 but not HER2 In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2-induced signaling and cell growth. Acquisition of HER2 upon development of resistance to neratinib in a breast cancer with an initial activating mutation suggests is a driver mutation. HER2-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib. We found an acquired gatekeeper mutation in a patient with -mutant breast cancer upon clinical progression on neratinib. We speculate that may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with -activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. .
©2017 American Association for Cancer Research.
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